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Antibody-Drug Conjugate

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https://www.readbyqxmd.com/read/28649690/enzymatic-conjugation-using-branched-linkers-for-constructing-homogeneous-antibody-drug-conjugates-with-high-potency
#1
Yasuaki Anami, Wei Xiong, Xun Gui, Mi Deng, Cheng Cheng Zhang, Ningyan Zhang, Zhiqiang An, Kyoji Tsuchikama
Antibody-drug conjugates (ADCs) are emerging therapeutic agents in the treatment of cancer, and various conjugation strategies and chemical linkers have been developed to efficiently construct ADCs. Despite previous extensive efforts for improving conjugation efficiency and ADC homogeneity, most ADC linkers developed to date load only single payloads. Branched linkers that can load multiple payload molecules have yet to be fully explored. It is logical to envisage that a multi-loading strategy allows for increase in drug-to-antibody ratio (DAR) with less chemical or enzymatic modification to the antibody structure compared to traditional linear linkers, leading to efficient ADC construction, minimal destabilization of the antibody structure, and enhanced ADC efficacy...
June 26, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28649658/niche-localized-tumor-cells-are-protected-from-her2-targeted-therapy-via-upregulation-of-an-anti-apoptotic-program-in-vivo
#2
Jason J Zoeller, Roderick T Bronson, Laura M Selfors, Gordon B Mills, Joan S Brugge
Several lines of evidence suggest that components of the tumor microenvironment, specifically basement membrane and extracellular matrix proteins, influence drug sensitivities. We previously reported differential drug sensitivity of tumor cells localized adjacent to laminin-rich extracellular matrix in three-dimensional tumor spheroid cultures. To evaluate whether differential intra-tumor responses to targeted therapy occur in vivo, we examined the sensitivity of human epidermal growth factor receptor 2-positive tumors to lapatinib using a previously described ductal carcinoma in situ-like model characterized by tumor cell confinement within ductal structures surrounded by an organized basement membrane...
2017: NPJ Breast Cancer
https://www.readbyqxmd.com/read/28649245/camelid-single-domain-antibodies-as-an-alternative-to-overcome-challenges-related-to-the-prevention-detection-and-control-of-neglected-tropical-diseases
#3
REVIEW
Carla F C Fernandes, Soraya Dos S Pereira, Marcos B Luiz, Juliana P Zuliani, Gilvan P Furtado, Rodrigo G Stabeli
Due mainly to properties such as high affinity and antigen specificity, antibodies have become important tools for biomedical research, diagnosis, and treatment of several human diseases. When the objective is to administer them for therapy, strategies are used to reduce the heterologous protein immunogenicity and to improve pharmacokinetic and pharmacodynamic characteristics. Size minimization contributes to ameliorate these characteristics, while preserving the antigen-antibody interaction site. Since the discovery that camelids produce functional antibodies devoid of light chains, studies have proposed the use of single domains for biosensors, monitoring and treatment of tumors, therapies for inflammatory and neurodegenerative diseases, drug delivery, or passive immunotherapy...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28648785/lc-ms-bioanalysis-of-trastuzumab-and-released-emtansine-using-nano-surface-and-molecular-orientation-limited-nsmol-proteolysis-and-liquid-liquid-partition-in-plasma-of-trastuzumab-emtansine-treated-breast-cancer-patients
#4
Noriko Iwamoto, Akihiko Shimomura, Kenji Tamura, Akinobu Hamada, Takashi Shimada
Antibody-drug conjugates (ADCs) consist of monoclonal antibody and cytotoxic drugs covalently attached via stable crosslinkers, and are prospective antibody drugs for cancer therapy. To cover the overall pharmacokinetic understanding of ADCs, both the antibody and the released drugs are necessary for practical clinical observation. The nano-surface and molecular-orientation limited (nSMOL) proteolysis is a universal approach for antibody bioanalysis that enable Fab-selective proteolysis, which maintains antibody sequence specificity while decreasing excess analyte peptides...
June 19, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28646659/analysis-of-recombinant-monoclonal-antibodies-in-hydrophilic-interaction-chromatography-a-generic-method-development-approach
#5
Balázs Bobály, Valentina D'Atri, Alain Beck, Davy Guillarme, Szabolcs Fekete
Hydrophilic interaction liquid chromatography (HILIC) is a well-established technique for the separation and analysis of small polar compounds. A recently introduced widepore stationary phase expanded HILIC applications to larger molecules, such as therapeutic proteins. In this paper, we present some generic HILIC conditions adapted for a wide range of FDA and EMA approved recombinant monoclonal antibody (mAb) species and for an antibody-drug conjugate (ADC). Seven approved mAbs possessing various isoelectric point (pI) and hydrophobicity as well as a cysteine conjugated ADC were used in this study...
June 15, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28646408/a-mechanism-based-pk-pd-model-for-hematological-toxicities-induced-by-antibody-drug-conjugates
#6
Sihem Ait-Oudhia, Weiyan Zhang, Donald E Mager
Antibody-drug conjugates (ADCs) are complex drug platforms composed of monoclonal antibodies (mAbs) conjugated to potent cytotoxic drugs (payloads) via chemical linkers, enabling selective payload delivery to neoplastic cells, resulting in improved efficacy and reduced toxicity. Brentuximab vedotin (Adcetris®, SGN-35) and adotrastuzumab emtansine (Kadcyla®, T-DM1) are the two FDA-approved and commercially available ADCs, and both drugs exhibit ADC-related thrombocytopenia and neutropenia. A pharmacokinetic/pharmacodynamic (PK/PD) model for ADCs was developed to identify the analyte from each ADC that is most associated with the observed hematopoietic toxicities and to determine the role of the apparent in vivo payload release rate on the severity of thrombocytopenia and neutropenia...
June 23, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28641516/updated-regulatory-considerations-for-nanomedicines
#7
Sankarankutty Subin, Venugopal Vijayan, Jaya Raja Kumar
BACKGROUND: Nanomedicine is a branch which deals with medicinal products, devices, non-biological complex drugs and antibody-nanoparticle conjugates and general health products that are manufactured using nanotechnology. OBJECTIVE: Nanomedicine provide the same efficacies as traditional medicines owing to their improved solubility and bioavailability with reduced dosages. However, there are currently safety concerns due to the difficulties related to nanomaterial characterization; this might be the reason for unawareness of such medicines among the patients...
June 14, 2017: Pharmaceutical Nanotechnology
https://www.readbyqxmd.com/read/28640063/pharmacodynamic-monitoring-of-tacrolimus-based-immunosuppression-in-cd14-monocytes-after-kidney-transplantation
#8
Nynke M Kannegieter, Dennis A Hesselink, Marjolein Dieterich, Gretchen N De Graav, Rens Kraaijeveld, Ajda T Rowshani, Pieter Jm Leenen, Carla C Baan
BACKGROUND: Monocytes significantly contribute to ischemia reperfusion injury and allograft rejection after kidney transplantation. However, the knowledge about the effects of immunosuppressive drugs on monocyte activation is limited. Conventional pharmacokinetic methods for immunosuppressive drug monitoring are not cell type-specific. In this study, phosphorylation of three signaling proteins was measured to determine the pharmacodynamic effects of immunosuppression on monocyte activation in kidney transplant patients...
June 19, 2017: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/28638777/heterobifunctional-dyes-highly-fluorescent-linkers-based-on-cyanine-dyes
#9
Virginia Wycisk, Katharina Achazi, Ole Hirsch, Christian Kuehne, Jens Dernedde, Rainer Haag, Kai Licha
Herein, we present a new synthetic route to cyanine-based heterobifunctional dyes and their application as fluorescent linkers between polymers and biomolecules. The synthesized compounds, designed in the visible spectral range, are equipped with two different reactive groups for highly selective conjugation under physiological conditions. By applying indolenine precursors with functionalized benzenes, we achieved water-soluble asymmetric cyanine dyes bearing maleimido and N-hydroxysuccinimidyl functionalities in a three-step synthesis...
June 2017: ChemistryOpen
https://www.readbyqxmd.com/read/28637474/arsenic-trioxide-inhibits-ebv-reactivation-and-promotes-cell-death-in-ebv-positive-lymphoma-cells
#10
Qinyan Yin, Mark Sides, Christopher H Parsons, Erik K Flemington, Joseph A Lasky
BACKGROUND: Epstein-Barr Virus (EBV) is associated with hematopoietic malignancies, such as Burkitt's lymphoma, post-transplantation lymphoproliferative disorder, and diffuse large B-cell lymphoma. The current approach for EBV-associated lymphoma involves chemotherapy to eradicate cancer cells, however, normal cells may be injured and organ dysfunction may occur with currently employed regimens. This research is focused on employing arsenic trioxide (ATO) as EBV-specific cancer therapy takes advantage of the fact the EBV resides within the malignant cells...
June 21, 2017: Virology Journal
https://www.readbyqxmd.com/read/28636382/development-of-efficient-chemistry-to-generate-site-specific-disulfide-linked-protein-and-peptide-payload-conjugates-application-to-thiomab%C3%A2-antibody-drug-conjugates
#11
Jack David Sadowsky, Thomas H Pillow, Jinhua Chen, Fang Fan, Changrong He, Yanli Wang, Gang Yan, Hui Yao, Zijin Xu, Shanique Martin, Donglu Zhang, Phillip Chu, Josefa Dela Cruz-Chuh, Aimee O'Donohue, Guangmin Li, Geoffrey Del Rosario, Jintang He, Luna Liu, Carl K Ng, Dian Su, Gail D Lewis Phillips, Katherine Ruth Kozak, Shang-Fan Yu, Keyang Xu, Douglas Leipold, John S Wai
Conjugation of small molecule payloads to specific cysteine residues on proteins via a disulfide bond represents an attractive strategy to generate redox-sensitive bioconjugates, which have value as potential diagnostic reagents or therapeutics. Advancement of such "direct-disulfide" bioconjugates to the clinic necessitates chemical methods to form disulfide connections efficiently, without byproducts. The disulfide connection must also be resistant to premature cleavage by thiols prior to arrival at the targeted tissue...
June 21, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28634286/conjugate-vaccine-immunotherapy-for-substance-use-disorder
#12
REVIEW
Paul T Bremer, Kim D Janda
Substance use disorder, especially in relation to opioids such as heroin and fentanyl, is a significant public health issue and has intensified in recent years. As a result, substantial interest exists in developing therapeutics to counteract the effects of abused drugs. A promising universal strategy for antagonizing the pharmacology of virtually any drug involves the development of a conjugate vaccine, wherein a hapten structurally similar to the target drug is conjugated to an immunogenic carrier protein...
July 2017: Pharmacological Reviews
https://www.readbyqxmd.com/read/28634245/targeting-nectin-4-in-bladder-cancer
#13
(no author information available yet)
Preliminary findings from a phase I clinical trial indicate that enfortumab vedotin, an investigational antibody-drug conjugate targeting nectin-4, shows considerable efficacy in metastatic urothelial carcinoma. Robust responses were seen even among patients with disease progression on platinum chemotherapy and/or immune checkpoint blockade.
June 20, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28633756/immunotherapy-the-wave-of-the-future-in-bladder-cancer
#14
Daniel P Petrylak
Urothelial cell carcinoma (UC) is one of the most common cancers and one of the most deadly. Metastatic UC is particularly hard to treat, because it is typically diagnosed when patients are elderly and have medical comorbidities. Many patients with metastatic UC are unable to receive cisplatin-based chemotherapy, due to older age at diagnosis and comorbidities, and even when platinum chemotherapy can be administered, it has limited success in prolonging survival. Recently, improved understanding of molecular targets and immunologic characteristics of urothelial tumor cells has resulted in new therapeutic approaches that may help optimize first- and second-line therapy...
June 2017: Clinical Genitourinary Cancer
https://www.readbyqxmd.com/read/28630216/fractionated-dosing-improves-preclinical-therapeutic-index-of-pyrrolobenzodiazepine-containing-antibody-drug-conjugates
#15
Mary Jane Hinrichs, Pauline M Ryan, Bo Zheng, Shameen Afif-Rider, Xiang-Qing Yu, Michele Gunsior, Haihong Zhong, Jay Harper, Binyam Bezabeh, Kapil Vashisht, Marlon Rebelatto, Molly Reed, Patricia C Ryan, Shannon Breen, Neki Patel, Cui Chen, Luke A Masterson, Arnaud Tiberghien, Philip W Howard, Nazzareno Dimasi, Rakesh Dixit
                Purpose:  To use preclinical models to identify a dosing schedule that improves tolerability of highly potent pyrrolobenzodiazepine dimers (PBD) antibody drug conjugates (ADCs) without compromising anti-tumor activity.  <p>                Experimental design:   A series of dose-fractionation studies were conducted to investigate the pharmacokinetic drivers of safety and efficacy of PBD ADCs in animal models.  The exposure-activity relationship was investigated in mouse xenograft models of human prostate cancer, breast and gastric cancer by comparing anti-tumor activity after single and fractionated dosing with tumor-targeting ADCs conjugated to SG3249, a potent PBD dimer...
June 19, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28627385/advances-in-antibody-drug-conjugates-a-new-era-of-targeted-cancer-therapy
#16
REVIEW
Samaresh Sau, Hashem O Alsaab, Sushil Kumar Kashaw, Katyayani Tatiparti, Arun K Iyer
Antibody-drug conjugates (ADCs), a potent class of anticancer therapeutics, comprise a high-affinity antibody (Ab) and cytotoxic payload coupled via a suitable linker for selective tumor cell killing. In the initial phase of their development, two ADCs, Mylotarg(®), and Adcetris(®) were approved by the US Food and Drug Administration (FDA) for treating hematological cancer, but the real breakthrough came with the discovery of the breast cancer-targeting ADC, Kadcyla(®). With advances in bioengineering, linker chemistry, and potent cytotoxic payload, ADC technology has become a more powerful tool for targeted cancer therapy...
June 13, 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/28625826/drug-discovery-and-therapeutic-delivery-for-the-treatment-of-b-and-t-cell-tumors
#17
Regan Stephenson, Ankur Singh
Hematological malignancies manifest as lymphoma, leukemia, and myeloma, and remain a burden on society. From initial therapy to endless relapse-related treatment, societal burden is felt not only in the context of healthcare cost, but also in the compromised quality of life of patients. Long-term therapeutic strategies have become the standard in keeping hematological malignancies at bay as these cancers develop resistance to each round of therapy with time. As a result, there is a continual need for the development of new drugs to combat resistant disease in order to prolong patient life, if not to produce a cure...
June 15, 2017: Advanced Drug Delivery Reviews
https://www.readbyqxmd.com/read/28622622/characterization-of-drug-load-variants-in-a-thiol-linked-antibody-drug-conjugate-using-multidimensional-chromatography
#18
Jonathan J Gilroy, Catherine M Eakin
The biological complexity associated with biotherapeutics such as antibody-drug conjugates (ADCs) requires extensive characterization to ensure product quality consistency, safety, and efficacy. ADCs generated via partial reduction of antibody interchain disulfide bonds result in a distribution of variants containing 0-8 conjugated drugs. Hydrophobic interaction chromatography (HIC) is a key analytical technique used to separate drug load variants of thiol linked ADCs and to calculate the average drug-to-antibody molar ratio (DAR)...
June 4, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/28607471/gemtuzumab-ozogamicin-in-acute-myeloid-leukemia
#19
REVIEW
C D Godwin, R P Gale, R B Walter
CD33 is variably expressed on leukemia blasts in almost all patients with acute myeloid leukemia (AML) and possibly leukemia stem cells in some. Efforts to target CD33 therapeutically have focused on gemtuzumab ozogamicin (GO; Mylotarg®), an antibody-drug conjugate delivering a DNA-damaging calicheamicin derivative. GO is most effective in acute promyelocytic leukemia but induces remissions in other AML types and received accelerated approval in the US in 2000. However, because a large follow-up study showed no survival improvement and increased early deaths the drug manufacturer voluntarily withdrew the US New Drug Application in 2010...
June 13, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28603750/quantitative-analysis-of-exosome-secretion-rates-of-single-cells
#20
Yu-Jui Chiu, Wei Cai, Tiffany Lee, Julia Kraimer, Yu-Hwa Lo
To study the inhomogeneity within a cell population including exosomes properties such as exosome secretion rate of cells and surface markers carried by exosomes, we need to quantify and characterize those exosomes secreted by each individual cell. Here we develop a method to collect and analyze exosomes secreted by an array of single cells using antibody-modified glass slides that are position-registered to each single cell. After each collection, anti-body conjugated quantum dots are used to label exosomes to allow counting and analysis of exosome surface proteins...
February 20, 2017: Bio-protocol
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