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antibody-drug conjugates

Kurt Schönfeld, Peter Herbener, Chantal Zuber, Thomas Häder, Katrin Bernöster, Christoph Uherek, Jörg Schüttrumpf
PURPOSE: Triple-negative breast cancer (TNBC) is related with a poor prognosis as patients do hardly benefit from approved therapies. CD138 (Syndecan-1) is upregulated on human breast cancers. Indatuximab ravtansine (BT062) is an antibody-drug-conjugate that specifically targets CD138-expressing cells and has previously shown clinical activity in multiple myeloma. Here we show indatuximab ravtansine as a potential mono- and combination therapy for TNBC. METHODS: The effects of indatuximab ravtansine were assessed in vitro in SK-BR-3 and T47D breast cancer cell lines...
April 17, 2018: Pharmaceutical Research
Fei Ding, Yangguang Gao, Xianran He, Yongmin Zhang
Since antibodies are one of the most successful classes of biopharmaceuticals for cancer treatment, it is very important to discuss the functionality and biological activity of endogenous antibodies in the diagnosis and treatment of the diseases. Antibodies act on tumor cells in diverse ways, including engaging in antibody-dependent effector mechanisms, internalizing to deliver toxins, and displaying direct effects on cells. In this review, we outline three kinds of antibody-based therapeutic systems, namely Antibody-based Drug Conjugates (Ab-DCs), Antibody-based Recruiting Small Molecules (Ab-RSMs) and Carbohydrate Epitopes Recruiting Natural Antibodies (CERNA) for human disease treatment and imaging...
March 1, 2018: Journal of Biomedical Nanotechnology
Simon Chang-Hao Tsao, Jing Wang, Yuling Wang, Andreas Behren, Jonathan Cebon, Matt Trau
Real-time monitoring of cancer cells' phenotypic evolution during therapy can provide vital tumour biology information for treatment management. Circulating tumour cell (CTC) analysis has emerged as a useful monitoring tool, but its routine usage is restricted by either limited multiplexing capability or sensitivity. Here, we demonstrate the use of antibody-conjugated and Raman reporter-coated gold nanoparticles for simultaneous labelling and monitoring of multiple CTC surface markers (named as "cell signature"), without the need for isolating individual CTCs...
April 16, 2018: Nature Communications
Yelena Kovtun, Gregory E Jones, Sharlene Adams, Lauren Harvey, Charlene A Audette, Alan Wilhelm, Chen Bai, Lingyun Rui, Rassol Laleau, Fenghua Liu, Olga Ab, Yulius Setiady, Nicholas C Yoder, Victor S Goldmacher, Ravi V J Chari, Jan Pinkas, Thomas Chittenden
The outlook for patients with refractory/relapsed acute myeloid leukemia (AML) remains poor, with conventional chemotherapeutic treatments often associated with unacceptable toxicities, including severe infections due to profound myelosuppression. Thus there exists an urgent need for more effective agents to treat AML that confer high therapeutic indices and favorable tolerability profiles. Because of its high expression on leukemic blast and stem cells compared with normal hematopoietic stem cells and progenitors, CD123 has emerged as a rational candidate for molecularly targeted therapeutic approaches in this disease...
April 24, 2018: Blood Advances
Jieliang Shen, Naiqiang Zhuo, Shenxi Xu, Zhaojun Song, Zhenming Hu, Jie Hao, Xiuming Guo
AIM: To improve nucleus pulposus cell-targeted therapy for intervertebral disc degeneration (IDD) by fabricating a novel kind of ultrasound (US)-mediated poly(lactic-co-glycolic acid) nanobubbles (NBs) as a means of targeted drug delivery. MATERIALS & METHODS: The resveratrol (RES)-embedded NBs were synthesized using a double-emulsion method. The active NP cell-targeting biomarker CDH2 antibody (AbCDH2) was further conjugated to the NBs using a carbodiimide method...
April 16, 2018: Nanomedicine
Federico Nichetti, Antonio Marra, Francesca Corti, Alessandro Guidi, Alessandra Raimondi, Natalie Prinzi, Filippo de Braud, Sara Pusceddu
Mesothelin is a tumor differentiation antigen, which is highly expressed in several solid neoplasms, including pancreatic cancer. Its selective expression on malignant cells and on only a limited number of healthy tissues has made it an interesting candidate for investigation as a diagnostic and prognostic biomarker and as a therapeutic target. Based on a strong preclinical rationale, a number of therapeutic agents targeting mesothelin have entered clinical trials, including immunotoxins, monoclonal antibodies, antibody-drug conjugates, cancer vaccines, and adoptive T cell therapies with chimeric antigen receptors...
April 14, 2018: Targeted Oncology
De-Zhi Li, Bing-Nan Han, Rui Wei, Gui-Yang Yao, Zhizhen Chen, Jie Liu, Terence C W Poon, Wu Su, Zhongyu Zhu, Dimiter S Dimitrov, Qi Zhao
Site-specific conjugation of small molecules to antibody molecules is a promising strategy for generation of antibody-drug conjugates. In this report, we describe the successful synthesis of a novel bifunctional molecule, 6-(azidomethyl)-2-pyridinecarboxyaldehyde (6-AM-2-PCA), which was used for conjugation of small molecules to peptides and antibodies. We demonstrated that 6-AM-2-PCA selectively reacted with N-terminal amino groups of peptides and antibodies. In addition, the azide group of 6-AM-2-PCA enabled copper-free click chemistry coupling with dibenzocyclooctyne-containing reagents...
April 13, 2018: MAbs
Kelly J Norsworthy, Chia-Wen Ko, Jee Eun Lee, Jiang Liu, Christy S John, Donna Przepiorka, Ann T Farrell, Richard Pazdur
On September 2, 2017, the U.S. Food and Drug Administration approved gemtuzumab ozogamicin (GO; Mylotarg; Pfizer, New York City, NY) for treatment of relapsed or refractory (R/R) CD33-positive acute myeloid leukemia (AML) in patients 2 years of age and older. GO is a CD33-directed antibody drug conjugate linked to the cytotoxic antibiotic calicheamicin. It originally received accelerated approval for treatment of older patients with relapsed CD33-positive AML in 2000, but it was withdrawn from the market in 2010 when the confirmatory trial failed to demonstrate clinical benefit among safety concerns, such as a higher rate of induction fatalities on the GO combination arm compared with chemotherapy alone...
April 12, 2018: Oncologist
Kenichiro Todoroki, Tomohiro Yamada, Hajime Mizuno, Toshimasa Toyo'oka
The increase in the use of therapeutic monoclonal antibodies (mAbs) and antibody-drug conjugates (ADCs) has made the detailed bioanalysis of these drugs essential not only for planning optimal therapeutic programs for clinical practice, but also for evaluating the biological equivalencies in the development of other biosimilars. The ligand binding assays that are widely in use now are being replaced rapidly by the highly accurate, sensitive, and selective analytical method using a mass spectrometer. This review will discuss the progress in and challenges observed during the development of a mass spectrometry-based bioanalytical method for therapeutic mAbs and ADCs...
2018: Analytical Sciences: the International Journal of the Japan Society for Analytical Chemistry
Nirnoy Dan, Saini Setua, Vivek K Kashyap, Sheema Khan, Meena Jaggi, Murali M Yallapu, Subhash C Chauhan
Chemotherapy is one of the major therapeutic options for cancer treatment. Chemotherapy is often associated with a low therapeutic window due to its poor specificity towards tumor cells/tissues. Antibody-drug conjugate (ADC) technology may provide a potentially new therapeutic solution for cancer treatment. ADC technology uses an antibody-mediated delivery of cytotoxic drugs to the tumors in a targeted manner, while sparing normal cells. Such a targeted approach can improve the tumor-to-normal tissue selectivity and specificity in chemotherapy...
April 9, 2018: Pharmaceuticals
Anna Pawełczyk, Katarzyna Sowa-Kasprzak, Dorota Olender, Lucjusz Zaprutko
The design and discovery of novel drug candidates are the initial and most probably the crucial steps in the drug development process. One of the tasks of medicinal chemistry is to produce new molecules that have a desired biological effect. However, even today the search for new pharmaceuticals is a very complicated process that is hard to rationalize. Literature provides many scientific reports on future prospects of design of potentially useful drugs. Many trends have been proposed for the design of new drugs containing different structures (dimers, heterodimers, heteromers, adducts, associates, complexes, biooligomers, dendrimers, dual-, bivalent-, multifunction drugs and codrugs, identical or non-identical twin drugs, mixed or combo drugs, supramolecular particles and various nanoindividuals...
April 6, 2018: International Journal of Molecular Sciences
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...
June 1, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Aditya V Gandhi, Keith J Arlotta, Hsiao-Nung Chen, Shawn C Owen, John F Carpenter
The commercially available antibody-drug conjugate (ADC) product, Kadcyla® is synthesized using a two-step reaction, wherein the linker is conjugated to native lysines on the monoclonal antibody (mAb) in step 1, followed by drug conjugation to the linker-modified antibody in step 2. In our study, we synthesized a lysine conjugated ADC (Syn-ADC) on the same trastuzumab scaffold as Kadcyla® using a one-step reaction. Mass spectrometry of both products revealed a sub-population of Kadcyla® containing free linkers conjugated to the mAb, but not conjugated to the drug, which were absent in the one-step reaction ADC product...
April 4, 2018: Journal of Pharmaceutical Sciences
Alireza Farasat, Fatemeh Rahbarizadeh, Davoud Ahmadvand, Saeed Ranjbar, Shahryar Khoshtinat Nikkhoi
Synergistic effect of combined antibodies targeting distinct epitopes of a particular tumour antigen has encouraged some clinical trial studies and is now considered as an effective platform for cancer therapy. Providing several advantages over conventional antibodies, variable domain of heavy chain of heavy chain antibodies (VH H) is now major tools in diagnostic and therapeutic applications. Active targeting of liposomal drugs is a promising strategy, resulting in enhanced binding and improved cytotoxicity of tumour cells...
April 6, 2018: Journal of Liposome Research
Deasy Pertiwi, Ronny Martien, - Sismindari, Hilda Ismail
Ribosome Inactivating Proteins (RIPs) isolated from Mirabilis jalapa L. (MJ protein) leaves showed high cytotoxic effect on malignant. Chitosan nanoparticles have frequently been used in protein delivery applications. The aim of this study was to develop targeted drug delivery system of RIP MJ for breast cancer therapy with chitosan nanoparticles conjugated antiEpCAM antibody. RIP MJ nanoparticles were prepared using low viscous chitosan and pectin using polyelectrolit complex method, followed by conjugation process with antiEpCAM antibody...
March 2018: Pakistan Journal of Pharmaceutical Sciences
Megan Laudenbach, Federico Baruffaldi, Christine Robinson, Philipp Carter, Davis Seelig, Carly Baehr, Marco Pravetoni
Vaccines offer an option to treat heroin and prescription opioid abuse and prevent fatal overdoses. Opioid vaccines elicit antibodies that block opioid distribution to the brain and reduce opioid-induced behavioral effects and toxicity. The major limitation to the translation of addiction vaccines is that efficacy is observed only in subjects achieving optimal drug-specific serum antibody levels. This study tested whether efficacy of a vaccine against oxycodone is increased by immunomodulators targeting key cytokine signaling pathways involved in B and T cell lymphocyte activation...
April 3, 2018: Scientific Reports
Elizabeth Diago-Navarro, Michael P Motley, Gonzalo Ruiz-Peréz, Winnie Yu, Julianne Austin, Bruna M S Seco, Guozhi Xiao, Aniska Chikhalya, Peter H Seeberger, Bettina C Fries
Carbapenem-resistant (CR) sequence type 258 (ST258) Klebsiella pneumoniae has become an urgent health care threat, causing an increasing number of high-mortality infections. Its resistance to numerous antibiotics and threat to immunocompromised patients necessitate finding new therapies to combat these infections. Previous successes in the laboratory, as well as the conservation of capsular polysaccharide (CPS) among the members of the ST258 clone, suggest that monoclonal antibody (MAb) therapy targeting the outer polysaccharide capsule of K...
April 3, 2018: MBio
Lawrence E L'Italien, Olivia Orozco, Tinya J Abrams, Lisa Cantagallo, Anu Connor, Jayesh Desai, Hilmar Ebersbach, Hans Gelderblom, Keith Hoffmaster, Emma Lees, Heiko Maacke, Siew Schleyer, Darko Skegro, Si Tuen Lee-Hoeflich
PURPOSE: Hypersensitivity reactions (HSR) were observed in three patients dosed in a phase I clinical trial treated with LOP628, a KIT targeted antibody drug conjugate. Mast cell degranulation was implicated as the root cause for the HSR. Underlying mechanism of this reported HSR was investigated with an aim to identifying potential mitigation strategies. EXPERIMENTAL DESIGN: Biomarkers for mast cell degranulation were evaluated in patient samples and in human peripheral blood cell-derived mast cell (PBC-MC) cultures treated with LOP628...
April 3, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Nida Akhtar, Kamla Pathak
BACKGROUND: Cervical cancer being the cancer of cervix is caused by the aberrant cell growth that acquires an ability to spread/ invade to other body parts as well. It has been reported to be the second most commonest cause of death and cancer as well among women. Based on the severity of the disease, treatment aspect needs to be explored more in order to overcome the limitations acquired by conventional treatment. Recently, nanocarriers based drug delivery systems including liposomes, nanofibres, metallic NPs, polymeric NPs, dendrimers, polymeric micelles, antibody-drug conjugates etc...
April 2, 2018: Recent Patents on Drug Delivery & Formulation
Mary Chacko Sunitha, Radhakrishnan Dhanyakrishnan, Bhaskara PrakashKumar, Kottayath Govindan Nevin
Doxorubicin (Dox) is a widely administered chemotherapeutic drug and incidences of cardiotoxicity associated with its administration have been of general concern. Extensive research proposes several mechanisms as a cause of Dox induced cardiotoxicity. However, none of these studies have been able to suggest a find one, cure all antidote for the same. To this end, several studies involving plant based compounds or natural products have gained acclaim for their ability to address at least one factor contributing to drug induced pathogenesis...
March 29, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
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