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antibody-drug conjugates

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https://www.readbyqxmd.com/read/28822152/-preparation-of-cd123-mono-antibody-modified-tanshinone-%C3%A2-a-loaded-immunoliposome-and-its-in-vitro-evaluation
#1
Yin Wang, Fu-Rong Liu, Hong-Lin Xiang, Hong Qing, Chen Chen, Sheng-Jun Mao, Hui Li
In the study, we developed a novel formulation, CD123 mono-antibody (mAb) modified tanshinone ⅡA loaded immunoliposome (CD123-TanⅡA-ILP) to achieve the targeted drug delivery for leukemia cells. Orthogonal test was used to optimize liposome preparation, and the TanⅡA-loaded PEGylated liposomes (TanⅡA-LP) of S100PC-Chol-(mPEG2000-DSPE)-TanⅡA at 19∶5∶1∶1 molar ratio were prepared by the thin film hydration-probe ultrasonic method. A post-insertion method was applied to prepare CD123-TanⅡA-ILP via thiolated mAb conjugated to the terminal of maleimide-PEG2000-DSPE...
June 2017: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
https://www.readbyqxmd.com/read/28822103/current-progress-in-innovative-engineered-antibodies
#2
REVIEW
William R Strohl
As of May 1, 2017, 74 antibody-based molecules have been approved by a regulatory authority in a major market. Additionally, there are 70 and 575 antibody-based molecules in phase III and phase I/II clinical trials, respectively. These total 719 antibody-based clinical stage molecules include 493 naked IgGs, 87 antibody-drug conjugates, 61 bispecific antibodies, 37 total Fc fusion proteins, 17 radioimmunoglobulins, 13 antibody fragments, and 11 immunocytokines. New uses for these antibodies are being discovered each year...
August 18, 2017: Protein & Cell
https://www.readbyqxmd.com/read/28821484/measurement-and-mathematical-characterization-of-cell-level-pharmacokinetics-of-antibody-drug-conjugates-a-case-study-with-trastuzumab-vc-mmae
#3
Aman P Singh, Dhaval K Shah
The main objective of this work was to understand and mathematically characterize the cellular disposition of a tool ADC, trastuzumab-vc-MMAE (T-vc-MMAE). Towards this goal, three different analytical methods were developed to measure the concentrations of different ADC related analytes in the media and cell lysate. An LC-MS/MS method was developed to quantify unconjugated drug (i.e. MMAE) concentrations, a forced deconjugation method was developed to quantify total drug concentrations, and an ELISA method was developed to quantify total antibody (i...
August 18, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28821272/novel-immunotherapies-for-adult-patients-with-b-lineage-acute-lymphoblastic-leukemia
#4
REVIEW
Guoqing Wei, Jiasheng Wang, He Huang, Yanmin Zhao
The past decade witnessed the rapid development of adult B-lineage acute lymphoblastic leukemia (ALL) treatment. Beyond the development of chemotherapy regimens, immunotherapy is starting a new era with unprecedented complete remission (CR) rate. Targeting B-lineage-specific surface markers such as CD19, CD20, CD22, or CD52, immunotherapy has been demonstrating promising clinical results. Among the immunotherapeutic methods, naked monoclonal antibodies (mAbs), antibody-drug conjugate (ADC), bispecific T cell engager (BiTE), and chimeric antigen receptor (CAR) T cells are the main types...
August 18, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28820579/site-specific-conjugation-to-native-and-engineered-lysines-in-human-immunoglobulins-by-microbial-transglutaminase
#5
Jared Spidel, Benjamin Vaessen, Earl Albone, Xin Cheng, Arielle Verdi, J Bradford Kline
The use of microbial transglutaminase (MTG) to produce site-specific antibody-drug conjugates (ADCs) has thus far focused on transamidation of engineered acyl donor glutamine residues in an antibody based on the hypothesis that the lower specificity of MTG for acyl acceptor lysines may result in transamidation of multiple native lysine residues, thereby yielding heterogeneous products. We investigated the utilization of native IgG lysines as acyl acceptor sites for glutamine-based acyl donor substrates. Of the approximately 80 lysines in multiple recombinant IgG monoclonal antibodies (mAbs), none were transamidated...
August 18, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28819447/targeting-activated-platelets-a-unique-and-potentially-universal-approach-for-cancer-imaging
#6
May Lin Yap, James D McFadyen, Xiaowei Wang, Nicholas A Zia, Jan David Hohmann, Melanie Ziegler, Yu Yao, Alan Pham, Matthew Harris, Paul S Donnelly, P Mark Hogarth, Geoffrey A Pietersz, Bock Lim, Karlheinz Peter
Rationale The early detection of primary tumours and metastatic disease is vital for successful therapy and is contingent upon highly specific molecular markers and sensitive, non-invasive imaging techniques. We hypothesized that the accumulation of activated platelets within tumours is a general phenomenon and thus represents a novel means for the molecular imaging of cancer. Here we investigate a unique single chain antibody (scFv), which specifically targets activated platelets, as a novel biotechnological tool for molecular imaging of cancer...
2017: Theranostics
https://www.readbyqxmd.com/read/28819027/combination-therapy-with-bispecific-antibodies-and-pd-1-blockade-enhances-the-antitumor-potency-of-t-cells
#7
Chien-Hsing Chang, Yang Wang, Rongxiu Li, Diane L Rossi, Donglin Liu, Edmund A Rossi, Thomas M Cardillo, David M Goldenberg
The DOCK-AND-LOCK (DNL®) method is a platform technology that combines recombinant engineering and site-specific conjugation to create multispecific, multivalent antibodies of defined composition with retained bioactivity. We have applied DNL® to generate a novel class of trivalent bispecific antibodies (bsAbs), each comprising an anti-CD3 scFv covalently conjugated to a stabilized dimer of different anti-tumor Fabs. Here we report the further characterization of two such constructs, (E1)-3s and (14)-3s, which activate T cells and target Trop-2- and CEACAM5-expressing cancer cells, respectively...
August 17, 2017: Cancer Research
https://www.readbyqxmd.com/read/28818506/development-and-evaluation-of-%C3%AE-galactosidase-sensitive-antibody-drug-conjugates
#8
Sergii Kolodych, Chloé Michel, Sébastien Delacroix, Oleksandr Koniev, Anthony Ehkirch, Jitka Eberova, Sarah Cianférani, Brigitte Renoux, Wojciech Krezel, Pauline Poinot, Christian D Muller, Sébastien Papot, Alain Wagner
The selective destruction of tumour cells while sparing healthy tissues is one of the main challenges in cancer therapy. Antibody-drug conjugates (ADCs) are arguably the most rapidly expanding class of targeted cancer therapies. Efficient drug conjugation and release technologies are essential for the development of these new therapeutic agents. In response to the ever-increasing demand for efficient drug release systems, we have developed a new class of β-galactosidase-cleavable linkers for ADCs. Within this framework, novel payloads comprising a galactoside linker, the monomethyl auristatin E (MMAE) and cysteine-reactive groups were synthesized, conjugated with trastuzumab and evaluated both in vitro and in vivo...
August 4, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28817371/phase-i-ii-trial-of-labetuzumab-govitecan-anti-ceacam5-sn-38-antibody-drug-conjugate-in-patients-with-refractory-or-relapsing-metastatic-colorectal-cancer
#9
Efrat Dotan, Steven J Cohen, Alexander N Starodub, Christopher H Lieu, Wells A Messersmith, Pamela S Simpson, Michael J Guarino, John L Marshall, Richard M Goldberg, J Randolph Hecht, William A Wegener, Robert M Sharkey, Serengulam V Govindan, David M Goldenberg, Jordan D Berlin
Purpose The objectives were to evaluate dosing schedules of labetuzumab govitecan, an antibody-drug conjugate targeting carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) for tumor delivery of 7-ethyl-10-hydroxycamptothecin (SN-38), in an expanded phase II trial of patients with relapsed or refractory metastatic colorectal cancer. Patients and Methods Eligible patients with at least one prior irinotecan-containing therapy received labetuzumab govitecan once weekly at 8 and 10 mg/kg, or two times per week at 4 and 6 mg/km on weeks 1 and 2 of 3-week repeated cycles...
August 17, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28814834/intracellular-trafficking-of-new-anticancer-therapeutics-antibody-drug-conjugates
#10
REVIEW
Muhammad Kalim, Jie Chen, Shenghao Wang, Caiyao Lin, Saif Ullah, Keying Liang, Qian Ding, Shuqing Chen, Jinbiao Zhan
Antibody-drug conjugate (ADC) is a milestone in targeted cancer therapy that comprises of monoclonal antibodies chemically linked to cytotoxic drugs. Internalization of ADC takes place via clathrin-mediated endocytosis, caveolae-mediated endocytosis, and pinocytosis. Conjugation strategies, endocytosis and intracellular trafficking optimization, linkers, and drugs chemistry present a great challenge for researchers to eradicate tumor cells successfully. This inventiveness of endocytosis and intracellular trafficking has given considerable momentum recently to develop specific antibodies and ADCs to treat cancer cells...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28813596/molecular-imaging-of-p-glycoprotein-in-chemoresistant-tumors-using-a-dual-modality-pet-fluorescence-probe
#11
Mengzhe Wang, Chengqiong Mao, Hui Wang, Xueying Ling, Zhanhong Wu, Zi-Bo Li, Xin Ming
Overexpression of P-glycoprotein (Pgp) has been considered a primary cause for multidrug resistance in a variety of cancers for three decades. However, clinical translation of Pgp targeted therapeutics has been hindered by lack of patient preselection based on the Pgp presence in tumors. We aim to develop a molecularly targeted probe for imaging tumoral Pgp in vivo with positron emission tomography (PET) and fluorescence, and to provide a tool for preselecting the patients with tumoral Pgp expression. Thus, a Pgp monoclonal antibody 15D3 was chemically modified with IRDye800 (IR800) and DOTA chelator...
August 16, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28811102/high-resolution-separations-of-charge-variants-and-disulfide-isomers-of-monoclonal-antibodies-and-antibody-drug-conjugates-using-ultra-high-voltage-capillary-electrophoresis-with-high-electric-field-strength
#12
W Hampton Henley, Yan He, J Scott Mellors, Nicholas G Batz, J Michael Ramsey, James W Jorgenson
Ultra-high voltage capillary electrophoresis with high electric field strength has been applied to the separation of the charge variants, drug conjugates, and disulfide isomers of monoclonal antibodies. Samples composed of many closely related species are difficult to resolve and quantify using traditional analytical instrumentation. High performance instrumentation can often save considerable time and effort otherwise spent on extensive method development. Ideally, the resolution obtained for a given CE buffer system scales with the square root of the applied voltage...
July 29, 2017: Journal of Chromatography. A
https://www.readbyqxmd.com/read/28810739/a-hexa-rhodium-metallopeptide-catalyst-for-site-specific-functionalization-of-natural-antibodies
#13
Jun Ohata, Zachary T Ball
Preparation of antibody-drug conjugates (ADCs), an emerging class of targeted biological hybrid agents, necessitates precise control of conjugation reactivity. Antibodies have complex multi-stranded architectures, and specific modification of natu-ral antibodies has proven quite challenging. Here, we demonstrate that cooperative activity of a multi-metallic metallopeptide enables efficient site-specific antibody functionalization, based on molecular recognition of the constant Fc region. This interplay of multiple metal centers enables introduction of an orthogonal alkyne handle into monoclonal or polyclonal antibodies from different species...
August 16, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28808917/development-of-a-translational-physiologically-based-pharmacokinetic-model-for-antibody-drug-conjugates-a-case-study-with-t-dm1
#14
Antari Khot, Jay Tibbitts, Dan Rock, Dhaval K Shah
Systems pharmacokinetic (PK) models that can characterize and predict whole body disposition of antibody-drug conjugates (ADCs) are needed to support (i) development of reliable exposure-response relationships for ADCs and (ii) selection of ADC targets with optimal tumor and tissue expression profiles. Towards this goal, we have developed a translational physiologically based PK (PBPK) model for ADCs, using T-DM1 as a tool compound. The preclinical PBPK model was developed using rat data. Biodistribution of DM1 in rats was used to develop the small molecule PBPK model, and the PK of conjugated trastuzumab (i...
August 14, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28801661/statistical-characterization-of-therapeutic-protein-modifications
#15
Tsung-Heng Tsai, Zhiqi Hao, Qiuting Hong, Benjamin Moore, Cinzia Stella, Jeffrey H Zhang, Yan Chen, Michael Kim, Theo Koulis, Gregory A Ryslik, Erik Verschueren, Fred Jacobson, William E Haskins, Olga Vitek
Peptide mapping with liquid chromatography-tandem mass spectrometry (LC-MS/MS) is an important analytical method for characterization of post-translational and chemical modifications in therapeutic proteins. Despite its importance, there is currently no consensus on the statistical analysis of the resulting data. In this manuscript, we distinguish three statistical goals for therapeutic protein characterization: (1) estimation of site occupancy of modifications in one condition, (2) detection of differential site occupancy between conditions, and (3) estimation of combined site occupancy across multiple modification sites...
August 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28798339/real-time-analysis-on-drug-antibody-ratio-of-antibody-drug-conjugates-for-synthesis-process-optimization-and-quality-control
#16
Yubo Tang, Feng Tang, Yang Yang, Lei Zhao, Hu Zhou, Jinhua Dong, Wei Huang
Drug-antibody ratio (DAR) of antibody-drug conjugates (ADCs) is important for their therapeutic efficacy and pharmacokinetics, therefore control on DAR in synthesis process is a key for ADC quality control. Although various analytical methods were reported, the real-time monitoring on DAR is still a challenge because time-consuming sample preparation is usually needed during the analysis. Antibody deglycosylation of ADC simplifies DAR measurement, however long-time PNGaseF digestion for deglycosylation hampers the real-time detection...
August 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28792782/emerging-antibody-drug-conjugates-for-treating-lymphoid-malignancies
#17
Anna Wolska-Washer, Pawel Robak, Piotr Smolewski, Tadeusz Robak
Antibody-drug conjugates (ADC) are monoclonal antibodies (Mabs) attached to biologically active drugs through specialized chemical linkers. They deliver and release cytotoxic agents at the tumor site, reducing the likelihood of systemic exposure and therefore toxicity. These agents should improve the potency of chemotherapy by increasing the accumulation of the cytotoxic drug within or near the neoplastic cells with reduced systemic effects. Areas covered and methods: A literature review was conducted using the MEDLINE database, PubMed, for articles in English examining Mabs, B-cell receptor pathway inhibitors and immunomodulating drugs...
August 9, 2017: Expert Opinion on Emerging Drugs
https://www.readbyqxmd.com/read/28791656/egfr-as-a-target-for-glioblastoma-treatment-an-unfulfilled-promise
#18
Manfred Westphal, Cecile L Maire, Katrin Lamszus
The receptor for epidermal growth factor (EGFR) is a prime target for cancer therapy across a broad variety of tumor types. As it is a tyrosine kinase, small molecule tyrosine kinase inhibitors (TKIs) targeting signal transduction, as well as monoclonal antibodies against the EGFR, have been investigated as anti-tumor agents. However, despite the long-known enigmatic EGFR gene amplification and protein overexpression in glioblastoma, the most aggressive intrinsic human brain tumor, the potential of EGFR as a target for this tumor type has been unfulfilled...
August 8, 2017: CNS Drugs
https://www.readbyqxmd.com/read/28776425/treatment-of-adult-acute-lymphoblastic-leukemia-with-inotuzumab-ozogamicin
#19
Shilpa Paul, Caitlin R Rausch, Hagop Kantarjian, Elias J Jabbour
Treatment of adult acute lymphoblastic leukemia (ALL) has largely relied on cytotoxic chemotherapy agents borrowed from successful treatment regimens of pediatric ALL. However, the high cure rates seen in pediatric ALL have not been replicated in adults. In recent years, the development of monoclonal antibodies targeting cell surface antigens, such as CD19 and CD20, have significantly improved outcomes when used alone or in combination with cytotoxic chemotherapy. With these novel agents come challenges in managing adverse events, understanding mechanisms of resistance and determining their optimal place in therapy alongside conventional chemotherapy and allogeneic stem cell transplant...
August 4, 2017: Future Oncology
https://www.readbyqxmd.com/read/28771632/refinement-of-immunizing-antigens-to-produce-functional-blocking-antibodies-against-the-ania-nitrite-reductase-of-neisseria-gonorrhoeae
#20
Lucy K Shewell, Freda E-C Jen, Michael P Jennings
The emergence of multi-drug resistant Neisseria gonorrhoeae has generated an urgent need for novel therapies or a vaccine to prevent gonococcal disease. In this study we investigate the potential of targeting the surface exposed nitrite reductase, AniA, to block activity by producing functional blocking antibodies. AniA activity is essential for anaerobic growth and biofilm formation of N. gonorrhoeae and functional blocking antibodies may prevent colonisation and disease. Seven peptides covering regions adjacent to the active site were designed based on the AniA structure...
2017: PloS One
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