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https://www.readbyqxmd.com/read/29148816/assessment-of-anti-piperacillin-igg-binding-to-structurally-related-drug-protein-adducts
#1
Mohammed Amali, Rosalind Jenkins, Xioali Meng, Lee Faulkner, Paul Whitaker, Daniel Peckham, B Kevin Park, Dean John Naisbitt
The risk of developing hypersensitivity to alternative antibiotics is a concern for penicillin hypersensitive patients and healthcare pro-viders. Herein we use piperacillin hypersensitivity as a model to explore the reactivity of drug-specific IgG against alternative β-lactam protein adducts. Mass spectrometry was used to show the drugs (amoxicillin, flucloxacillin, benzyl penicillin, aztreonam and pipera-cillin) bind to similar lysine residues on the protein carrier bovine serum albumin. However, the hapten-specific IgG antibodies found in piperacillin hypersensitive patient plasma did not bind to other β-lactam protein conjugates...
November 17, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/29146698/characterization-of-site-specifically-conjugated-monomethyl-auristatin-e-and-duocarmycin-based-anti-psma-antibody-drug-conjugates-for-treatment-of-psma-expressing-tumors
#2
Susanne Lütje, Danny Gerrits, Janneke D Molkenboer-Kuenen, Ken Herrmann, Giulio Fracasso, Marco Colombatti, Otto C Boerman, Sandra Heskamp
Rationale: Prostate cancer (PCa) is the most common cancer in men worldwide. In general, PCa responds poorly to chemotherapy. Therefore, antibody-drug conjugates (ADCs) have been developed to specifically deliver highly cytotoxic drugs to the tumor. As the prostate-specific membrane antigen (PSMA) is overexpressed in PCa, it represents a promising target for ADC-based therapies. The aim of this study was to evaluate the therapeutic efficacy of site-specifically conjugated duocarmycin- and monomethyl auristatin E (MMAE)-based anti-PSMA ADCs with drug-antibody ratios (DARs) of 2 and 4...
November 16, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/29142346/conjugation-of-antibodies-with-radiogold-nanoparticles-as-an-effector-targeting-agents-in-radiobioconjugate-cancer-therapy-optimized-labeling-and-biodistribution-results
#3
Pankaj Garg, Daya Kishore Hazra
Purpose of the Study: Drug accessibility to the tumor cells is an important area of concern with an anticipation of increasing the efficacy of the drug to be delivered to a specific site. The biogenesis of gold nanoparticles using plant-mediated phytochemical extracts and their possible linkage to cancer antibodies with an aim at delivering the conjugate specifically to the tumor-associated antigen is the basic objective of the research. Materials and Methodology: Radiolabeling of antibodies with gold nanoparticles was carried out by a protocol, and the labeling extent of antibodies was compared with that of a radiogold solution to ordinary particulate size (AuNO-Ab)...
October 2017: Indian Journal of Nuclear Medicine: IJNM: the Official Journal of the Society of Nuclear Medicine, India
https://www.readbyqxmd.com/read/29142069/cat-02-106-a-site-specifically-conjugated-anti-cd22-antibody-bearing-an-mdr1-resistant-maytansine-payload-yields-excellent-efficacy-and-safety-in-preclinical-models
#4
Penelope M Drake, Adam Carlson, Jesse M McFarland, Stefanie Banas, Robyn M Barfield, Wesley Zmolek, Yun Cheol Kim, Betty C B Huang, Romas Kudirka, David Rabuka
Hematologically-derived tumors make up ~10% of all newly-diagnosed cancer cases in the U.S. Of these, the non-Hodgkin lymphoma (NHL) designation describes a diverse group of cancers that collectively rank among the top 10 most commonly diagnosed cancers worldwide. Although long-term survival trends are improving, there remains a significant unmet clinical need for treatments to help patients with relapsed or refractory disease, one cause of which is drug efflux through upregulation of xenobiotic pumps, such as MDR1...
November 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29142066/characterization-of-sgn-cd123a-a-potent-cd123-directed-antibody-drug-conjugate-for-acute-myeloid-leukemia
#5
Fu Li, May Kung Sutherland, Changpu Yu, Roland B Walter, Lori Westendorf, John Valliere-Douglass, Lucy Pan, Ashley Cronkite, Django Sussman, Kerry Klussman, Michelle Ulrich, Martha E Anderson, Ivan J Stone, Weiping Zeng, Mechthild Jonas, Timothy S Lewis, Maitrayee Goswami, Sa A Wang, Peter D Senter, Che-Leung Law, Eric J Feldman, Dennis R Benjamin
Treatment choices for acute myeloid leukemia (AML) patients resistant to conventional chemotherapies are limited and novel therapeutic agents are needed. Interleukin-3 receptor alpha (IL-3Rα, or CD123) is expressed on the majority of AML blasts and there is evidence that its expression is increased on leukemic relative to normal hematopoietic stem cells, which makes it an attractive target for antibody-based therapy. Here we report the generation and preclinical characterization of SGN-CD123A, an antibody-drug conjugate utilizing the pyrrolobenzodiazepine dimer (PBD) linker and a humanized CD123 antibody with engineered cysteines for site-specific conjugation...
November 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29138558/%C3%AE-v%C3%AE-3-integrin-targeted-micellar-mertansine-prodrug-effectively-inhibits-triple-negative-breast-cancer-in-vivo
#6
Ping Zhong, Xiaolei Gu, Ru Cheng, Chao Deng, Fenghua Meng, Zhiyuan Zhong
Antibody-mertansine (DM1) conjugates (AMCs) are among the very few active targeting therapeutics that are approved or clinically investigated for treating various cancers including metastatic breast cancer. However, none of the AMCs are effective for the treatment of triple-negative breast cancers (TNBCs). Here, we show that cRGD-decorated, redox-activatable micellar mertansine prodrug (cRGD-MMP) can effectively target and deliver DM1 to αvβ3 integrin overexpressing MDA-MB-231 TNBC xenografts in nude mice, resulting in potent tumor growth inhibition...
2017: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/29133623/immu-140-a-novel-sn-38-antibody-drug-conjugate-targeting-hla-dr-mediates-dual-cytotoxic-effects-in-hematological-cancers-and-malignant-melanoma
#7
Thomas M Cardillo, Serengulam V Govindan, Maria B Zalath, Diane L Rossi, Yang Wang, Chien-Hsing Chang, David M Goldenberg
HLA-DR is a member of the MHC class II antigen family expressed on hematological and solid tumors.  Antibodies directed against HLA-DR have demonstrated some clinical success, but toxicities limited development.  IMMU-140 is an anti-HLA-DR antibody-drug conjugate comprised of the active metabolite of irinotecan, SN-38, conjugated to a humanized anti-HLA-DR IgG4 antibody (IMMU-114); the IgG4 naked antibody is devoid of immune functions. Our aim was to determine if SN-38, the metabolite of a drug not commonly used in hematopoietic cancers, would be effective and safe when targeted to HLA-DR-expressing tumors...
November 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29133014/incorporation-of-brentuximab-vedotin-into-first-line-treatment-of-advanced-classical-hodgkin-s-lymphoma-final-analysis-of-a-phase-2-randomised-trial-by-the-german-hodgkin-study-group
#8
Dennis A Eichenauer, Annette Plütschow, Stefanie Kreissl, Martin Sökler, Johannes C Hellmuth, Julia Meissner, Stephan Mathas, Max S Topp, Karolin Behringer, Wolfram Klapper, Georg Kuhnert, Markus Dietlein, Carsten Kobe, Michael Fuchs, Volker Diehl, Andreas Engert, Peter Borchmann
BACKGROUND: A high proportion of patients with relapsed classical Hodgkin's lymphoma achieve a response with the antibody-drug conjugate brentuximab vedotin, and the drug is well tolerated. We modified the escalated BEACOPP regimen (eBEACOPP; bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and implemented brentuximab vedotin with the aim to reduce toxic effects while maintaining the protocol's efficacy. METHODS: We did an open-label, multicentre, randomised phase 2 study at 20 study sites in Germany...
November 10, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/29127674/pharmacotherapeutic-management-of-pediatric-lymphoma
#9
REVIEW
Christine Mauz-Körholz, Natascha Ströter, Julia Baumann, Ante Botzen, Katharina Körholz, Dieter Körholz
Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) comprise approximately 15% of all childhood malignancies. Cure rates for both lymphoma entities have evolved tremendously during the last couple of decades, raising the 5-year survival rates to almost 100% for HL and to 85% for NHL. The mainstay therapy for both malignancies is still chemotherapy-with different regimens recommended for different types of disease. In HL, combined modality treatment, i.e., chemotherapy followed by radiotherapy, has long been the standard regimen...
November 10, 2017: Paediatric Drugs
https://www.readbyqxmd.com/read/29123949/targeting-il-5r%C3%AE-with-antibody-conjugates-reveals-a-strategy-for-imaging-and-therapy-for-invasive-bladder-cancer
#10
Michel Paquette, Luis-Guillermo Vilera-Perez, Simon Beaudoin, Nadia Ekindi-Ndongo, Pierre-Luc Boudreaut, Marc-Andre Bonin, Marie-Claude Battista, M'hamed Bentourkia, Angel F Lopez, Roger Lecomte, Eric Marsault, Brigitte Guérin, Robert Sabbagh, Jeffrey V Leyton
Despite the high interest and concern due to an increasing incidence and death rate, patients who develop muscle invasive bladder cancer (MIBC) have few options available. However, the past decade has produced many candidate bladder tumor-specific markers but further development of these markers is still needed for creating effective targeted medications to solve this urgent need. Interleukin-5 receptor α-subunit (IL-5Rα) has recently been reported to be involved in MIBC progression. Thus, we aimed to validate IL-5Rα as a target for antibody-conjugates to better manage patients with MIBC...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/29120405/site-specific-antibody-conjugation-for-adc-and-beyond
#11
REVIEW
Qun Zhou
Antibody-drug conjugates (ADCs) have become a promising class of antitumor agents with four conjugates being approved by regulatory agencies for treating cancer patients. To improve the conventional conjugations that are currently applied to generate these heterogeneous products, various site-specific approaches have been developed. These methods couple cytotoxins or chemotherapeutic drugs to specifically defined sites in antibody molecules including cysteine, glutamine, unnatural amino acids, short peptide tags, and glycans...
November 9, 2017: Biomedicines
https://www.readbyqxmd.com/read/29119409/recent-developments-in-adc-technology-preclinical-studies-signal-future-clinical-trends
#12
REVIEW
Penelope M Drake, David Rabuka
The antibody-drug conjugate (ADC) field is in a transitional period. Older approaches to conjugate composition and dosing regimens still dominate the ADC clinical pipeline, but preclinical work is driving a rapid evolution in how we strategize to improve efficacy and reduce toxicity towards better therapeutic outcomes. These advances are largely based upon a body of investigational studies that together offer a deeper understanding of the absorption, distribution, metabolism, and excretion (ADME) and drug metabolism and pharmacokinetics (DMPK) fates of both the intact conjugate and its small-molecule component...
November 8, 2017: BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
https://www.readbyqxmd.com/read/29116596/antibody-drug-conjugates-for-the-treatment-of-solid-tumors-clinical-experience-and-latest-developments
#13
Aiko Nagayama, Leif W Ellisen, Bruce Chabner, Aditya Bardia
Antibody-drug conjugates (ADCs) are complex immunoconjugates designed to selectively deliver toxic small molecules preferentially to cancer cells. These immunoconjugates consist of a monoclonal antibody - directed to a tumor antigen - and a cytotoxic agent that is conjugated to the antibody via a molecular linker. Following the binding to a specific antigen on the surface of cancer cells, the conjugate is internalized and releases its cytotoxic payload to kill the malignant cell. ADCs that have gained regulatory approval from the US Food and Drug Administration (FDA) include brentuximab vedotin for CD30-positive Hodgkin's lymphoma and trastuzumab emtansine for human epidermal growth factor receptor 2 (HER2)-positive breast cancer...
November 8, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/29113154/synergistic-inhibitory-effects-of-an-engineered-antibody-like-molecule-atf-fc-and-trastuzumab-on-tumor-growth-and-invasion-in-a-human-breast-cancer-xenograft-mouse-model
#14
Hongwei Zhou, Hongwei Wang, Guangyuan Yu, Zhihong Wang, Xi Zheng, Haifeng Duan, Junzhong Sun
The overexpression of the oncogene human epidermal growth factor receptor 2 (HER-2) has been associated with decreased disease-free survival and is a marker of poor prognosis of invasive breast cancer. Although the high efficacy of trastuzumab, a drug that targets the HER-2 oncogene, has been widely recognized, the efficiency of the treatment remains at ~30%. Therefore, novel effective treatments are required for patients with recurrent metastatic breast cancer. The present study aimed to investigate the effects of an engineered antibody-like molecule administered alone or in combination with trastuzumab on the tumor growth and metastasis of HER-2-positive breast cancer...
November 2017: Oncology Letters
https://www.readbyqxmd.com/read/29112410/pyrrolobenzodiazepine-dimer-antibody-drug-conjugates-synthesis-and-evaluation-of-non-cleavable-drug-linkers
#15
Stephen J Gregson, Luke A Masterson, Binqing Wei, Thomas H Pillow, Susan D Spencer, Gyoung-Dong Kang, Shang-Fan Yu, Helga Raab, Jeffrey Lau, Guangmin Li, Gail D Lewis Phillips, Janet Gunzner-Toste, Brian S Safina, Rachana Ohri, Martine Darwish, Katherine R Kozak, Josefa Dela Cruz-Chuh, Andrew Polson, John A Flygare, Philip W Howard
Three rationally designed pyrrolobenzodiazepine (PBD) drug-linkers have been synthesized via intermediate 19 for use in antibody-drug conjugates (ADCs). They lack a cleavable trigger in the linker and consist of a maleimide for cysteine antibody conjugation, a hydrophilic spacer, and either an alkyne (6), triazole (7) or piperazine (8) link to the PBD. In vitro IC50s were 11-48 ng/mL in HER2 3+ SK-BR-3 and KPL-4 (7 inactive) for the anti-HER2 ADCs (HER2 0 MCF7, all inactive) and 0.10-1.73 µg/mL (7 inactive) in CD22 3+ BJAB and WSU-DLCL2 for anti-CD22 ADCs (CD22 0 Jurkat, all inactive at low doses)...
November 7, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29102679/cutaneous-t-cell-lymphomas-focusing-on-novel-agents-in-relapsed-and-refractory-disease
#16
REVIEW
Lisa Argnani, Alessandro Broccoli, Pier Luigi Zinzani
Patients with relapsed or refractory cutaneous T-cell lymphoma (CTCL) display a dismal prognosis and their therapy represents an unmet medical need, as the best treatment strategy is yet to be determined. Exciting data on novel targeted agents are now emerging from recently concluded and ongoing clinical trials in patients with relapsed and refractory CTCL. Three FDA approved compounds are used as single agents including the oral retinoid bexarotene and histone deacetylase inhibitors romidepsin and vorinostat...
October 28, 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/29102228/macrocyclic-pyrrolobenzodiazepine-dimers-as-antibody-drug-conjugate-payloads
#17
Andrew F Donnell, Yong Zhang, Erik M Stang, Donna D Wei, Andrew J Tebben, Heidi L Perez, Gretchen M Schroeder, Chin Pan, Chetana Rao, Robert M Borzilleri, Gregory D Vite, Sanjeev Gangwar
Macrocyclic pyrrolobenzodiazepine dimers were designed and evaluated for use as antibody-drug conjugate payloads. Initial structure-activity exploration established that macrocyclization could increase the potency of PBD dimers compared with non-macrocyclic analogs. Further optimization overcame activity-limiting solubility issues, leading to compounds with highly potent (picomolar) activity against several cancer cell lines. High levels of in vitro potency and specificity were demonstrated with an anti-mesothelin conjugate...
October 16, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29102080/prospects-of-pasylation%C3%A2-for-the-design-of-protein-and-peptide-therapeutics-with-extended-half-life-and-enhanced-action
#18
Michaela Gebauer, Arne Skerra
Pharmacokinetic (PK) extension is no longer just a means to create improved second generation biologics (so-called biobetters), but constitutes an accepted strategy in biopharmaceutical drug development today. Although PEGylation has become a widely applied methodology to furnish therapeutic proteins and peptides with prolonged plasma half-life, the immunogenicity and missing biodegradability of this synthetic polymer has prompted an evident need for alternatives. PASylation is based on biological polypeptides made of the small l-amino acids Pro, Ala and/or Ser (PAS), which adopt a random coil structure in aqueous buffers with surprisingly similar biophysical properties as PEG...
September 15, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29098867/a-review-of-mirvetuximab-soravtansine-in-the-treatment-of-platinum-resistant-ovarian-cancer
#19
Kathleen N Moore, Lainie P Martin, David M O'Malley, Ursula A Matulonis, Jason A Konner, Ignace Vergote, Jose F Ponte, Michael J Birrer
Resistance to platinum-based therapy poses a significant clinical challenge for the management of advanced ovarian cancer, a leading cause of cancer mortality among women. Mirvetuximab soravtansine is a novel antibody-drug conjugate that targets folate receptor-α, a validated molecular target for therapeutic intervention in this disease. Here, we examine mirvetuximab soravtansine's mechanism of action and pharmacology, and review its clinical evaluation in ovarian cancer to date. We focus on the favorable tolerability and encouraging signals of efficacy that have emerged, most notably in patients with platinum-resistant disease...
November 3, 2017: Future Oncology
https://www.readbyqxmd.com/read/29090524/outcome-of-pediatric-patients-with-acute-lymphoblastic-leukemia-lymphoblastic-lymphoma-with-hypersensitivity-to-pegaspargase-treated-with-pegylated-erwinia-asparaginase-pegcrisantaspase-a-report-from-the-children-s-oncology-group
#20
Rachel E Rau, ZoAnn Dreyer, Mi Rim Choi, Wei Liang, Roman Skowronski, Krishna P Allamneni, Meenakshi Devidas, Elizabeth A Raetz, Peter C Adamson, Susan M Blaney, Mignon L Loh, Stephen P Hunger
BACKGROUND: Erwinia asparaginase is a Food and Drug Administration approved agent for the treatment of acute lymphoblastic leukemia (ALL) for patients who develop hypersensitivity to Escherichia coli derived asparaginases. Erwinia asparaginase is efficacious, but has a short half-life, requiring six doses to replace one dose of the most commonly used first-line asparaginase, pegaspargase, a polyethylene glycol (PEG) conjugated E. coli asparaginase. Pegcristantaspase, a recombinant PEGylated Erwinia asparaginase with improved pharmacokinetics, was developed for patients with hypersensitivity to pegaspargase...
November 1, 2017: Pediatric Blood & Cancer
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