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Antibody drug conjugation

Sebastian Andris, Matthias Rüdt, Jonas Rogalla, Michaela Wendeler, Jürgen Hubbuch
The conjugation reaction of monoclonal antibodies (mAbs) with small-molecule drugs is a central step during production of antibody-drug conjugates (ADCs). The ability to monitor this step in real time can be advantageous for process understanding and control. Here, we propose a method based on UV/Vis spectroscopy in conjunction with partial least squares (PLS) regression for non-invasive monitoring of conjugation reactions. In experiments, the method was applied to conjugation reactions with two surrogate drugs in microplate format as well as at 20 ml scale...
October 12, 2018: Journal of Biotechnology
Yaping Wang, Ming Yang, Junmin Qian, Weijun Xu, Jinlei Wang, Guanghui Hou, Lijie Ji, Aili Suo
Combination of chemotherapy and photodynamic therapy has emerged as a promising anticancer strategy. Polysaccharide-based nanoparticles are being intensively explored as drug carriers for different forms of combination therapy. In this study, novel multifunctional polysaccharide-based nanocomplexes were prepared from aldehyde-functionalized hyaluronic acid and hydroxyethyl chitosan via sequential self-assembly method. Stable nanocomplexes were obtained through both Schiff's base bond and electrostatic interactions...
January 1, 2019: Carbohydrate Polymers
(no author information available yet)
The MET-targeting antibody-drug conjugate telisotuzumab vedotin (Teliso-V) is well tolerated in patients.
October 12, 2018: Cancer Discovery
Hideto Tamura
Multiple myeloma (MM) involves the immune dysregulation not only of B cells but also of NK, T, and dendritic cells. Furthermore, the number of regulatory T and myeloid-derived immunosuppressive cells, which are associated with disease progression, also increases. Immunomodulatory drugs (IMiDs) such as lenalidomide and pomalidomide exhibit an antimyeloma effect and improve the immune status. Thus, IMiD-enhanced antibody-dependent cell cytotoxicity increases the cytotoxic activity of monoclonal antibody treatment...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Takahiro Yamauchi
The mainstay of therapeutic modalities of acute myeloid leukemia (AML) includes intensive chemotherapies and allogeneic hematopoietic cell transplantation. The gold standard of the induction treatment is a regular dose of cytarabine plus anthracycline, and several courses of consolidation therapy are administered. Allogeneic hematopoietic cell transplantation is employed in patients with intermediate-poor risks. No new drugs have been introduced to the treatment of AML for nearly 30 years. However, in 2017, the US Food and Drug Administration approved four novel drugs for treating AML: FLT3 inhibitor midostaurin, IDH2 inhibitor enasidenib, liposomal cytarabine-daunorubicin CPX-351, and revived antibody-drug conjugate gemtuzumab ozogamicin...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
You Lang Zhou, Luzhong Zhang, Zhou Zhou, Wei Liu, Yang Lu, Shumin He, Yajuan Cui, Yongwei Qin, Minhui Hua
The mechanism of Mycobacterium tuberculosis ( M.tb ) evasion of host cell remains elusive. Several microRNAs that are involved in this complex process were identified. miRNA interference-based therapeutics represents an attractive challenge and shows huge potential for disorder treatment. In this study, we found that miR-124-3p expression is significantly decreased in microglia after Mycobacterium marinum ( M.m ) infection. To achieve better target transfection effect, a CD11b antibody and PEI modified nanoparticles-based Nano platform had been developed...
December 1, 2018: Journal of Biomedical Nanotechnology
Chunhui Liang, Lushuai Zhang, Wene Zhao, Linlin Xu, Yaoxia Chen, Jiafu Long, Fuqiang Wang, Ling Wang, Zhimou Yang
Antibody-based medicines and nanomedicines are very promising for cancer therapy due to the high specificity and efficacy of antibodies. However, antibody-drug conjugates and antibody-modified nanomaterials frequently suffer from low drug loading and loss of functions due to the covalent modification of the antibody. A novel and versatile strategy to prepare supramolecular nanomaterials by the coassembly of an affibody (antiHER2) and drug-peptide amphiphiles is reported here. During the enzyme-instructed self-assembly process, the drug-peptide amphiphile can coassemble with the affibody, resulting in supramolecular nanofibers in hydrogels...
October 9, 2018: Advanced Healthcare Materials
Kimio Yonesaka, Naoki Takegawa, Satomi Watanabe, Koji Haratani, Hisato Kawakami, Kazuko Sakai, Yasutaka Chiba, Naoyuki Maeda, Takashi Kagari, Kenji Hirotani, Kazuto Nishio, Kazuhiko Nakagawa
EGFR tyrosine kinase inhibitors (TKIs) are standard therapy for EGFR-mutant non-small cell lung cancer (NSCLC); however, these tumours eventually acquire chemoresistance. U3-1402 is an anti-HER3 antibody-drug conjugate with a novel topoisomerase I inhibitor, DXd. In the current study, we evaluated the anticancer efficacy of U3-1402 in EGFR-mutant NSCLC cells with acquired resistance to EGFR-TKIs. HCC827GR5 and PC9AZDR7 are EGFR-TKI-resistant clones for gefitinib and osimertinib, respectively. U3-1402 alone or in combination with the EGFR-TKI erlotinib demonstrated potent anticancer efficacy in HCC827GR5 cells using an in vitro growth inhibition assay and in vivo xenograft mouse model...
October 9, 2018: Oncogene
Yimamu Maimaitili, Aki Inase, Yoshiharu Miyata, Akihito Kitao, Yu Mizutani, Seiji Kakiuchi, Yohei Shimono, Yasuyuki Saito, Takashi Sonoki, Hironobu Minami, Hiroshi Matsuoka
Gemtuzumab ozogamicin (GO), the first antibody-drug conjugate (ADC), has attracted the interest of hematologists because more than 90% of acute myeloid leukemia (AML) blasts express its target, CD33. Although GO and subsequently developed ADCs depend on lysosomes for activation, lysosome number and activity in tumor cells has not been well elucidated. In this study, we investigated whether an mTORC1/2 kinase inhibitor, PP242, which was reported to activate lysosomal function, potentiates the cytotoxicity of GO in AML cells...
October 2, 2018: Leukemia Research
Changyong Yang, Xiaoping Zhao, Xing Sun, Jinlong Li, Weiqiang Wang, Lianshan Zhang, Shaohua Gou
1. The in vivo pharmacokinetics (PK) profiles of a novel c-Met antibody-drug conjugate (ADC), SHR-A1403, were investigated and characterized in mice, rats and monkeys. 2. Serum concentrations of ADC and total antibody were detected using validated ELISA methods. The results showed low systemic clearance of both ADC and total antibody in all three species as reflected by gradual decrease in serum concentrations. Half-life (t1/2 ) of ADC ranged from 4.6 to 11.3 days in the three species. 3. Tissue distribution study in tumor-bearing mice showed high accumulation of 125 I-SHR-A1403 in tumor tissues over the other organs/tissues, indicating the favourable safety of SHR-A1403 and characteristics of an ADC drug...
October 9, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Chengqiong Mao, Ping Qu, Michael J Miley, Yan Zhao, Zibo Li, Xin Ming
P-glycoprotein (Pgp) has been considered as a major cause of cancer multidrug resistance; however, clinical solutions to overcome this drug resistance do not exist despite the tremendous endeavors. The lack of cancer specificity is a main reason for clinical failure of conventional approaches. Targeted photodynamic therapy (PDT) is highly cancer specific by combining antibody targeting and locoregional light irradiation. We aimed to develop Pgp-targeted PDT using antibody-photosensitizer conjugates made of a recombinant Fab fragment...
October 9, 2018: Biomaterials Science
Narendra Padhan
Immunoblotting has become a routine technique in many laboratories for protein characterization from biological samples. The following protocol provides an alternative strategy, capillary isoelectric focusing (cIEF), with many advantages compared to conventional immunoblotting. This is an antibody-based, automated, rapid, and quantitative method in which a complete western blotting procedure takes place inside an ultrathin capillary. This technique does not require a gel to transfer to a membrane, stripping of blots, or x-ray films, which are typically required for conventional immunoblotting...
September 19, 2018: Journal of Visualized Experiments: JoVE
Fen He, Nachuan Wen, Daipeng Xiao, Jianhua Yan, Hongjie Xiong, Shundong Cai, Zhenbao Liu, Yanfei Liu
Aptamers are single-stranded DNA or RNA with 20-100 nucleotides in length that can specifically bind to target molecules via formed three-dimensional structures. These innovative targeting molecules have attracted an increasing interest in biomedical field. Compared to traditional protein antibodies, aptamers have several advantages, such as small size, high binding affinity, specificity, good biocompatibility, high stability and low immunogenicity, which all contribute to their wide application in biomedical field...
October 8, 2018: Current Medicinal Chemistry
Lars Mecklenburg
Antibody-drug conjugates (ADCs) are an emerging class of anticancer therapeutics, delivering highly cytotoxic molecules directly to cancer cells. ADCs are composed of an antibody, a small molecule drug, and a linker attaching one to another. Antibodies are directed to a large variety of antigens overexpressed on tumor cells, tumor vasculature, or tumor-supporting stroma. After internalization, the ADC is transferred to lysosomes where the cytotoxic component is released, finally killing the target cell. All ADCs are administered via intravenous injection...
October 7, 2018: Toxicologic Pathology
Ying Fu, Mitchell Ho
Currently, four antibody-drug conjugates (ADCs) are approved by the Food and Drug Administration or the European Medicine Agency to treat cancer patients. More than 60 ADCs are in clinical development for cancer therapy. More than 60% of ADCs in clinical trials employ microtubule inhibitors as their payloads. A better understanding of payloads other than microtubule inhibitors, especially DNA-damaging agents, is important for further development of ADCs. In this review, we highlight an emerging trend of using DNA-damaging agents as payloads for ADCs...
September 2018: Antibody therapeutics
Soohyun Kim, Hyori Kim, Dong Hyun Jo, Jeong Hun Kim, Su Ree Kim, Dongmin Kang, Dobeen Hwang, Junho Chung
Antibody selection for antibody-drug conjugates (ADCs) has traditionally depended on its internalization into the target cell, although ADC efficacy also relies on recycling of the receptor-ADC complex, endo-lysosomal trafficking, and subsequent linker/antibody proteolysis. In this study, we observed that a bispecific anti-murine platelet-derived growth factor receptor beta (mPDGFRβ) x cotinine single-chain variable fragment (scFv)-kappa constant region (Cκ )-scFv fusion protein and cotinine-duocarmycin can form an ADC-like complex to induce cytotoxicity against mPDGFRβ expressing cells...
October 4, 2018: Methods: a Companion to Methods in Enzymology
Sonia Pernas, Romualdo Barroso-Sousa, Sara M Tolaney
Significant advances have occurred in the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer that have changed its natural history. The addition of trastuzumab to standard therapy has dramatically improved the prognosis for patients with early stage, HER2-positive breast cancer to unprecedented survival outcomes. Yet, long-term follow-up data from adjuvant pivotal trials indicate that 15-24% of patients still develop recurrent disease. Most of the research has focused on the addition of novel anti-HER2 drugs to standard therapy, including studies evaluating the monoclonal antibody pertuzumab; the antibody-drug conjugate trastuzumab-emtansine (T-DM1); the selective, reversible HER2/epidermal growth factor receptor kinase inhibitor lapatinib; or the irreversible pan-HER2 inhibitor neratinib...
October 6, 2018: Cancer
Malin Källsten, Rafael Hartmann, Konstantin Artemenko, Sara Bergström Lind, Fredrik Lehmann, Jonas Bergquist
Antibody-drug conjugates (ADCs) are an emerging type of biotherapeutics that utilize multiple tissue-specific antibodies combined with a range of linker designs to enable the transportation and selective release of cytotoxic drugs in close proximity to tumours. Consisting of antibodies conjugated to small drug molecules through a variety of linkers, ADCs are chemically complex analytes. Here we present a unique experimental comparison of four techniques for ADC analysis: hydrophobic interaction chromatography (HIC-UV/Vis), reversed phase liquid chromatography mass spectrometry (RPLC-MS), using either a QToF or an Orbitrap analyser, and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS)...
October 5, 2018: Analyst
Carolin Wollschlaeger, Ivo Meinhold-Heerlein, Xiaojing Cong, Karen Braeutigam, Stefano Di Fiore, Felix Zeppernick, Torsten Klockenbring, Elmar Stickeler, Stefan Barth, Ahmad Fawzi Hussain
Antibody-based diagnostic and therapeutic reagents armed with effector molecules such as dyes and drugs offer hope in the battle against cancer. Several site-specific conjugation methods have been developed to equip antibodies with such effector molecules, but they tend to be expensive and involve multiple reaction steps. The conjugation of two different effector molecules to a single antibody also remains a major challenge. Here we describe a simple, controlled and robust method for the dual site-specific conjugation of an antibody with two effector molecules in a single-pot reaction using the self-labeling SNAP and CLIP protein tags...
October 5, 2018: Bioconjugate Chemistry
Elena Cini, Valentina Faltoni, Elena Petricci, Maurizio Taddei, Laura Salvini, Giuseppe Giannini, Loredana Vesci, Ferdinando Maria Milazzo, Anna Maria Anastasi, Gianfranco Battistuzzi, Rita De Santis
We describe here two novel antibody-drug conjugates loaded with the HDAC inhibitor ST7612AA1 (IC50 equal to 0.07 μM on NCI-H460 cells), a thiol-based molecule with a moderate toxicity in vivo . Two payloads were prepared using cleavable and non-cleavable linkers. After anchoring to cetuximab through amide bond with lysines, the resulting HDAC inhibitor-antibody conjugates showed ability to recognize EGFR and efficient internalization in tumor cells. Both ADCs induced sensible increment of histones 3 and 4 and alpha-tubulin acetylation...
August 21, 2018: Chemical Science
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