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Antibody drug conjugates

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https://www.readbyqxmd.com/read/28926240/antineoplastic-agents-605-isoquinstatins
#1
George R Pettit, Noeleen Melody, Jean-Charles Chapuis
In order to further explore quinoline-type structural modification of the powerful anticancer drug dolastatin 10, an Indian Ocean sea hare constituent and parent molecule of the very successful antibody drug conjugate (ADC) Adcetris, our recent quinstatin study has been extended by replacing the quinoline ring with an isoquinoline. The resulting isoquinstatins (4-6) were modified to N-terminal desmethylisoquinstatins (7-9) and, in turn, bonded to appropriate linker units to give linker-desmethylisoquinstatin conjugates 11-13 in preparation for eventual monoclonal antibody attachment...
September 19, 2017: Journal of Natural Products
https://www.readbyqxmd.com/read/28924691/pharmacokinetic-considerations-for-antibody-drug-conjugates-against-cancer
#2
REVIEW
Paul Malik, Colin Phipps, Andrea Edginton, Jonathan Blay
Antibody-drug conjugates (ADCs) are ushering in the next era of targeted therapy against cancer. An ADC for cancer therapy consists of a potent cytotoxic payload that is attached to a tumour-targeted antibody by a chemical linker, usually with an average drug-to-antibody ratio (DAR) of 3.5-4. The theory is to deliver potent cytotoxic payloads directly to tumour cells while sparing healthy cells. However, practical application has proven to be more difficult. At present there are only two ADCs approved for clinical use...
September 18, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28923397/the-two-novel-dll4-targeting-antibody-drug-conjugates-mvm03-and-mgd03-show-potent-anti-tumour-activity-in-breast-cancer-xenograft-models
#3
Shijing Wang, Rihong Zhou, Fumou Sun, Renjie Li, Min Wang, Min Wu
The anti-human Delta-like 4 (DLL4) monoclonal antibody MMGZ01 has a high affinity to hrDLL4 and arrests the DLL4-mediated human umbilical vein endothelial cell (HUVEC) phenotype, promotes immature vessels, and effectively reduces breast cancer cell growth in vivo. To develop a much more effective therapy, we conjugated MMGZ01 with two small-molecule cytotoxic agents, i.e., monomethyl auristatin E (MMAE) and doxorubicin (DOX), with different linkers to generate antibody-drug conjugates (ADCs), i.e., MMGZ01-vc-MMAE (named MvM03) and MMGZ01-GMBS-DOX (named MGD03), that are more potent therapeutic agents than naked antibody therapeutic agents...
September 15, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28923100/checkpoint-inhibitor-is-active-against-large-cell-neuroendocrine-carcinoma-with-high-tumor-mutation-burden
#4
Victoria E Wang, Anatoly Urisman, Lee Albacker, Siraj Ali, Vincent Miller, Rahul Aggarwal, David Jablons
BACKGROUND: Large cell neuroendocrine tumor (LCNEC) of the lung is a rare and aggressive tumor similar to small cell lung cancer (SCLC). Thus, it is often treated similarly to SCLC in the front-line setting with a platinum doublet. However, treatment for patients beyond the first line remains undefined. CASE PRESENTATION: We report the case of a patient with stage IB LCNEC (PD-L1 negative but positive for PD-L1 amplification and tumor mutation burden high) who progressed after adjuvant chemotherapy after surgery and subsequent therapy with an antibody drug conjugate targeting a neuroendocrine-specific cell surface marker but achieved a significant and durable response with pembrolizumab, a humanized IgG4 monoclonal anti-PD-1 antibody...
September 19, 2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28921867/polymer-cancerostatics-targeted-with-an-antibody-fragment-bound-via-a-coiled-coil-motif-in-vivo-therapeutic-efficacy-against-murine-bcl1-leukemia
#5
Michal Pechar, Robert Pola, Olga Janoušková, Irena Sieglová, Vlastimil Král, Milan Fábry, Barbora Tomalová, Marek Kovář
A BCL1 leukemia-cell-targeted polymer-drug conjugate with a narrow molecular weight distribution consisting of an N-(2-hydroxypropyl)methacrylamide copolymer carrier and the anticancer drug pirarubicin is prepared by controlled radical copolymerization followed by metal-free click chemistry. A targeting recombinant single chain antibody fragment (scFv) derived from a B1 monoclonal antibody is attached noncovalently to the polymer carrier via a coiled coil interaction between two complementary peptides. Two pairs of coiled coil forming peptides (abbreviated KEK/EKE and KSK/ESE) are used as linkers between the polymer-pirarubicin conjugate and the targeting protein...
September 15, 2017: Macromolecular Bioscience
https://www.readbyqxmd.com/read/28921650/antibody-drug-conjugates-as-cancer-therapeutics-past-present-and-future
#6
Heather E Vezina, Monette Cotreau, Tae H Han, Manish Gupta
Antibody-drug conjugates (ADCs) represent an innovative therapeutic approach that provides novel treatment options and hope for patients with cancer. By coupling monoclonal antibodies (mAbs) to cytotoxic small-molecule payloads with a plasma-stable linker, ADCs offer the potential for increased drug specificity and fewer off-target effects than systemic chemotherapy. As evidence for the potential of these therapies, many new ADCs are in various stages of clinical development. Because their structure poses unique challenges to pharmacokinetic and pharmacodynamic characterization, it is critical to recognize the differences between ADCs and conventional chemotherapy in the design of ADC clinical development strategies...
October 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28918591/platform-model-describing-pharmacokinetic-properties-of-vc-mmae-antibody-drug-conjugates
#7
Matts Kågedal, Leonid Gibiansky, Jian Xu, Xin Wang, Divya Samineni, Shang-Chiung Chen, Dan Lu, Priya Agarwal, Bei Wang, Ola Saad, Neelima Koppada, Bernard M Fine, Jin Y Jin, Sandhya Girish, Chunze Li
Antibody-drug conjugates (ADCs) developed using the valine-citrulline-MMAE (vc-MMAE) platform, consist of a monoclonal antibody (mAb) covalently bound with a potent anti-mitotic toxin (MMAE) through a protease-labile vc linker. Recently, clinical data for a variety of vc-MMAE ADCs has become available. The goal of this analysis was to develop a platform model that simultaneously described antibody-conjugated MMAE (acMMAE) pharmacokinetic (PK) data from eight vc-MMAE ADCs, against different targets and tumor indications; and to assess differences and similarities of model parameters and model predictions, between different compounds...
September 16, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28915667/assessment-of-near-infrared-fluorophores-to-study-the-biodistribution-and-tumor-targeting-of-an-il13-receptor-%C3%AE-2-antibody-by-fluorescence-molecular-tomography
#8
Parul Gupta, Jo-Ann Wentland, Mauricio Leal, Dangshe Ma, Rachel Roach, Antonio Esparza, Lindsay King, Mary E Spilker, Cedo Bagi, Christopher T Winkelmann, Anand Giddabasappa
Non-invasive imaging using radiolabels is a common technique used to study the biodistribution of biologics. Due to the limited shelf-life of radiolabels and the requirements of specialized labs, non-invasive optical imaging is an attractive alternative for preclinical studies. Previously, we demonstrated the utility of fluorescence molecular tomography (FMT) an optical imaging modality in evaluating the biodistribution of antibody-drug conjugates. As FMT is a relatively new technology, few fluorophores have been validated for in vivo imaging...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28911823/towards-antibody-drug-conjugates-and-prodrug-strategies-with-extracellular-stimuli-responsive-drug-delivery-in-the-tumor-microenvironment-for-cancer-therapy
#9
REVIEW
Nicolas Joubert, Caroline Denevault-Sabourin, Francesca Bryden, Marie-Claude Viaud-Massuard
The design of innovative anticancer chemotherapies with superior antitumor efficacy and reduced toxicity continues to be a challenging endeavor. Recently, the success of Adcetris(®) and Kadcyla(®) made antibody-drug conjugates (ADCs) serious contenders to reach the envied status of Paul Ehrlich's "magic bullet". However, ADCs classically target overexpressed and internalizing antigens at the surface of cancer cells, and in solid tumors are associated with poor tumor penetration, insufficient targeting in heterogeneous tumors, and appearance of several resistance mechanisms...
August 23, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28910151/synthesis-positron-emission-tomography-imaging-and-therapy-of-diabody-targeted-drug-lipid-nanoparticles-in-a-prostate-cancer-murine-model
#10
Patty Wong, Lin Li, Junie Chea, Melissa K Delgado, Erasmus Poku, Barbara Szpikowska, Nicole Bowles, Megan Minnix, David Colcher, Jeffrey Y C Wong, John E Shively, Paul J Yazaki
The blood clearance of chemotherapeutic drugs such as doxorubicin (Dox) can be extended by incorporation into lipid nanoparticles (LNPs) and further improved by tumor targeting with antibody fragments. We used positron emission tomography (PET) imaging in a murine prostate cancer model to evaluate tumor targeting of LNPs incorporating Dox and antiprostate-specific membrane antigen (PSMA) diabodies. Dox-LNPs were generated by mixing or covalent attachment to water soluble distearoylphosphatidyl ethanolamine-polyethylene glycol (DSPE-PEG)2000...
September 2017: Cancer Biotherapy & Radiopharmaceuticals
https://www.readbyqxmd.com/read/28904834/methionine-mediated-synthesis-of-magnetic-nanoparticles-and-functionalization-with-gold-quantum-dots-for-theranostic-applications
#11
Arūnas Jagminas, Agnė Mikalauskaitė, Vitalijus Karabanovas, Jūrate Vaičiūnienė
Biocompatible superparamagnetic iron oxide nanoparticles (NPs) through smart chemical functionalization of their surface with fluorescent species, therapeutic proteins, antibiotics, and aptamers offer remarkable potential for diagnosis and therapy of disease sites at their initial stage of growth. Such NPs can be obtained by the creation of proper linkers between magnetic NP and fluorescent or drug probes. One of these linkers is gold, because it is chemically stable, nontoxic and capable to link various biomolecules...
2017: Beilstein Journal of Nanotechnology
https://www.readbyqxmd.com/read/28903943/therapeutic-potential-of-sgn-cd19b-a-pbd-based-anti-cd19-drug-conjugate-for-treatment-of-b-cell-malignancies
#12
Maureen C Ryan, Maria Corinna Palanca-Wessels, Brian Schimpf, Kristine A Gordon, Heather Kostner, Brad Meyer, Changpu Yu, Heather Van Epps, Dennis Benjamin
Patients with relapsed/refractory B-cell malignancies such as non-Hodgkin lymphoma (B-NHL) or acute lymphoblastic leukemia (B-ALL) have a poor prognosis. Despite measurable clinical activity with new targeted therapies, many patients do not achieve a complete or durable response suggesting an opportunity to improve upon existing therapies. Here we describe SGN-CD19B, a pyrrolobenzodiazepine (PBD)-based anti-CD19 antibody drug conjugate (ADC) being investigated for treatment of B-cell malignancies, which has improved potency compared to other ADCs...
September 13, 2017: Blood
https://www.readbyqxmd.com/read/28898695/identification-of-gpc2-as-an-oncoprotein-and-candidate-immunotherapeutic-target-in-high-risk-neuroblastoma
#13
Kristopher R Bosse, Pichai Raman, Zhongyu Zhu, Maria Lane, Daniel Martinez, Sabine Heitzeneder, Komal S Rathi, Nathan M Kendsersky, Michael Randall, Laura Donovan, Sorana Morrissy, Robyn T Sussman, Doncho V Zhelev, Yang Feng, Yanping Wang, Jennifer Hwang, Gonzalo Lopez, Jo Lynne Harenza, Jun S Wei, Bruce Pawel, Tricia Bhatti, Mariarita Santi, Arupa Ganguly, Javed Khan, Marco A Marra, Michael D Taylor, Dimiter S Dimitrov, Crystal L Mackall, John M Maris
We developed an RNA-sequencing-based pipeline to discover differentially expressed cell-surface molecules in neuroblastoma that meet criteria for optimal immunotherapeutic target safety and efficacy. Here, we show that GPC2 is a strong candidate immunotherapeutic target in this childhood cancer. We demonstrate high GPC2 expression in neuroblastoma due to MYCN transcriptional activation and/or somatic gain of the GPC2 locus. We confirm GPC2 to be highly expressed on most neuroblastomas, but not detectable at appreciable levels in normal childhood tissues...
September 11, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28898689/scratching-the-surface-of-immunotherapeutic-targets-in-neuroblastoma
#14
Clare F Malone, Kimberly Stegmaier
In this issue of Cancer Cell, Bosse et al. report GPC2 as a therapeutic target in neuroblastoma. They show that GPC2 is selectively expressed on the cell surface of neuroblastoma and is a dependency in this disease. Moreover, they demonstrate the therapeutic potential of an antibody-drug conjugate targeting GPC2.
September 11, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28898067/ligand-targeted-drug-delivery
#15
Madduri Srinivasarao, Philip S Low
Safety and efficacy constitute the major criteria governing regulatory approval of any new drug. The best method to maximize safety and efficacy is to deliver a proven therapeutic agent with a targeting ligand that exhibits little affinity for healthy cells but high affinity for pathologic cells. The probability of regulatory approval can conceivably be further enhanced by exploiting the same targeting ligand, conjugated to an imaging agent, to select patients whose diseased tissues display sufficient targeted receptors for therapeutic efficacy...
September 12, 2017: Chemical Reviews
https://www.readbyqxmd.com/read/28895394/antineoplastic-agents-604-the-path-of-quinstatin-derivatives-to-antibody-drug-conjugates
#16
George R Pettit, Noeleen Melody, Jean-Charles Chapuis
To further evaluate the exceptional cancer cell growth inhibition by the quinstatins, of which one of the series, quinstatin 8, approaches the exceptional cytotoxic activity of the parent dolastatin 10 (1), four of the quinstatins have been converted to desmethyl derivatives. Three of the four (4, 5, and 8 [7b-d]) were next bonded to the linker (8) employed in the synthesis of the very successful and structurally related anticancer drug Adcetris (3). Owing to these structural modifications, a next step could be taken by bonding to a monoclonal antibody, thereby producing an antibody drug conjugate (ADC) related to Adcetris structurally but with the possibility of a wider spectrum of activity and utility...
September 12, 2017: Journal of Natural Products
https://www.readbyqxmd.com/read/28893601/seek-destroy-use-of-targeting-peptides-for-cancer-detection-and-drug-delivery
#17
Vadim Le Joncour, Pirjo Laakkonen
Accounting for 16 million new cases and 9 million deaths annually, cancer leaves a great number of patients helpless. It is a complex disease and still a major challenge for the scientific and medical communities. The efficacy of conventional chemotherapies is often poor and patients suffer from off-target effects. Each neoplasm exhibits molecular signatures - sometimes in a patient specific manner - that may completely differ from the organ of origin, may be expressed in markedly higher amounts and/or in different location compared to the normal tissue...
September 1, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28888101/what-s-new-in-sclc-a-review
#18
REVIEW
Bryan Oronsky, Tony R Reid, Arnold Oronsky, Corey A Carter
A few years ago the answer to the question in the title of this review would have been, "unfortunately not much" or even "nothing", likely eliciting knowing nods of agreement from oncologists. For the last 3 decades, SCLC has been notorious for its lack of progress, as drug after drug, over 60 of them, in fact, including inhibitors of VEGF, IGFR, mTOR, EGFR and HGF has failed and fallen by the wayside due to little or no impact on PFS or OS, while SCLC's cousin, NSCLC, has notched success after success with a spate of targeted treatment and immunotherapy regulatory approvals...
September 6, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28885827/attachment-site-cysteine-thiol-pka-is-a-key-driver-for-site-dependent-stability-of-thiomab-tm-antibody-drug-conjugates
#19
Breanna S Vollmar, Binqing Wei, Rachana Ohri, Jianhui Zhou, Jintang He, Shang-Fan Yu, Douglas Leipold, Ely Cosino, Sharon Yee, Aimee Fourie-O'Donohue, Guangmin Li, Gail D Lewis Phillips, Katherine Ruth Kozak, Amrita Kamath, Keyang Xu, Genee Lee, Greg A Lazar, Hans K Erickson
Incorporation of cysteines into antibodies by mutagenesis allows for the direct conjugation of small molecules to specific sites on the antibody via disulfide bonds. The stability of the disulfide bond linkage between the small molecule and the antibody is highly dependent on the location of the engineered cysteine in either the heavy chain (HC) or light chain (LC) of the antibody. Here, we explore the basis for this site-dependent stability. We evaluated the in vivo efficacy and pharmacokinetics of five different cysteine mutants of trastuzumab conjugated to a pyrrolobenzodiazepine (PBD) via disulfide bonds...
September 8, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28885014/synthesis-and-evaluation-of-dolastatin-10-analogues-containing-heteroatoms-on-the-amino-acid-side-chains
#20
Julien Dugal-Tessier, Stuart D Barnscher, Akira Kanai, Brian A Mendelsohn
Synthetic analogues of the natural occurring dolastatin 10 are of great interest in cancer due to their potent in vitro activity and their uses as payloads in antibody drug conjugates (ADCs). Modification of the dolastatin 10 core scaffold has mainly focused on modifications of the P1, N-terminus, and P5, C-terminus, with minimal attention to the P2 subunit. In this paper we discuss the introduction of heteroatoms to the P2 side chain, which results in potent activity in vitro. The most active compounds contained azides in the P2 unit and required a phenylalanine-derived P5 subunit...
September 8, 2017: Journal of Natural Products
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