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antibody-drug conjugates

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https://www.readbyqxmd.com/read/29230672/the-role-of-b-cell-maturation-antigen-in-the-biology-and-management-of-and-as-a-potential-therapeutic-target-in-multiple-myeloma
#1
Eric Sanchez, Emily J Smith, Moryel A Yashar, Saurabh Patil, Mingjie Li, Autumn L Porter, Edward J Tanenbaum, Remy E Schlossberg, Camilia M Soof, Tara Hekmati, George Tang, Cathy S Wang, Haiming Chen, James R Berenson
B-cell maturation antigen (BCMA) was originally identified as a cell membrane receptor, expressed exclusively on late stage B-cells and plasma cells (PCs). Investigations of BCMA as a target for therapeutic intervention in multiple myeloma (MM) were initiated in 2007, using cSG1 as a naked antibody (Ab) as well as an Ab-drug conjugate (ADC) targeting BCMA, ultimately leading to ongoing clinical studies for previously treated MM patients. Since then, multiple companies have developed anti-BCMA-directed ADCs...
December 11, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/29227683/discovery-of-peptidomimetic-antibody-drug-conjugate-linkers-with-enhanced-protease-specificity
#2
Binqing Wei, Janet Gunzner-Toste, Hui Yao, Tao Wang, Jing Wang, Zijin Xu, Jinhua Chen, John Wai, Jim Nonomiya, Siao Ping Tsai, Josefa Dela Cruz-Chuh, Katherine Ruth Kozak, Yichin Liu, Shang-Fan Yu, Jeff Lau, Guangmin Li, Gail D Lewis Phillips, Doug Leipold, Amrita Kamath, Dian Su, Keyang Xu, Charles Eigenbrot, Stefan Steinbacher, Rachana Ohri, Helga Raab, Leanna R Staben, Guiling Zhao, John A Flygare, Thomas H Pillow, Vishal Verma, Brian Salvatore Safina
Antibody-Drug Conjugates (ADCs) have become an important therapeutic modality for oncology, with three approved by the FDA and over 60 others in clinical trials. Despite the progress, improvements in ADC therapeutic index are desired. Peptide-based ADC linkers that are cleaved by lysosomal proteases have shown sufficient stability in serum, and effective payload-release in targeted cells. If the linker can be preferentially hydrolyzed by tumor-specific proteases, safety margin may improve. However, the use of peptide-based linkers limits our ability to modulate protease specificity...
December 11, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29227302/the-target-invites-a-foe-antibody-drug-conjugates-in-gynecologic-oncology
#3
Maira P Campos, Gottfried E Konecny
PURPOSE OF REVIEW: Antibody-drug conjugates (ADCs) represent a promising new class of cancer therapeutics. Currently more than 60 ADCs are in clinical development, however, only very few trials focus on gynecologic malignancies. In this review, we summarize the most recent advances in ADC drug development with an emphasis on how this progress relates to patients diagnosed with gynecologic malignancies and breast cancer. RECENT FINDINGS: The cytotoxic payloads of the majority of the ADCs that are currently in clinical trials for gynecologic malignancies or breast cancer are auristatins (MMAE, MMAF), maytansinoids (DM1, DM4), calicheamicin, pyrrolobenzodiazepines and SN-38...
December 8, 2017: Current Opinion in Obstetrics & Gynecology
https://www.readbyqxmd.com/read/29224502/brentuximab-vedotin-with-chemotherapy-for-stage-iii-or-iv-hodgkin-s-lymphoma
#4
Joseph M Connors, Wojciech Jurczak, David J Straus, Stephen M Ansell, Won S Kim, Andrea Gallamini, Anas Younes, Sergey Alekseev, Árpád Illés, Marco Picardi, Ewa Lech-Maranda, Yasuhiro Oki, Tatyana Feldman, Piotr Smolewski, Kerry J Savage, Nancy L Bartlett, Jan Walewski, Robert Chen, Radhakrishnan Ramchandren, Pier L Zinzani, David Cunningham, Andras Rosta, Neil C Josephson, Eric Song, Jessica Sachs, Rachael Liu, Hina A Jolin, Dirk Huebner, John Radford
Background Brentuximab vedotin is an anti-CD30 antibody-drug conjugate that has been approved for relapsed and refractory Hodgkin's lymphoma. Methods We conducted an open-label, multicenter, randomized phase 3 trial involving patients with previously untreated stage III or IV classic Hodgkin's lymphoma, in which 664 were assigned to receive brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) and 670 were assigned to receive doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). The primary end point was modified progression-free survival (the time to progression, death, or noncomplete response and use of subsequent anticancer therapy) as adjudicated by an independent review committee...
December 10, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/29223444/association-of-vedolizumab-level-anti-drug-antibodies-and-%C3%AE-4%C3%AE-7-occupancy-with-response-in-patients-with-inflammatory-bowel-diseases
#5
Bella Ungar, Uri Kopylov, Miri Yavzori, Ella Fudim, Orit Picard, Adi Lahat, Daniel Coscas, Matti Waterman, Ola Haj-Natour, Noam Orbach-Zingboim, Ren Mao, Minhu Chen, Yehuda Chowers, Rami Eliakim, Shomron Ben-Horin
BACKGROUND & AIMS: There are few data available on the real-life pharmacokinetic and pharmacodynamics features of vedolizumab, a monoclonal antibody against integrin α4β7. We performed a prospective study of patients with inflammatory bowel diseases (IBD) treated with vedolizumab to determine serum drug concentrations, formation of anti-vedolizumab antibodies (AVAs), and integrin α4β7 saturation. METHODS: We performed a prospective study of 106 patients with IBD (67 with Crohn's disease and 39 with ulcerative colitis) treated with vedolizumab from September 2014 through March 2017 at 2 tertiary medical centers in Israel...
December 6, 2017: Clinical Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/29221137/ev20-sap-a-novel-anti-her-3-antibody-drug-conjugate-displays-promising-antitumor-activity-in-melanoma
#6
Emily Capone, Francesco Giansanti, Sara Ponziani, Alessia Lamolinara, Manuela Iezzi, Annamaria Cimini, Francesco Angelucci, Rossana La Sorda, Vincenzo De Laurenzi, Pier Giorgio Natali, Rodolfo Ippoliti, Stefano Iacobelli, Gianluca Sala
Melanoma is the most biologically aggressive skin cancer of well established constitutive and induced resistance to pharmacological treatment. Despite the recent progresses in immunotherapies, many advanced metastatic melanoma patients still face a significant mortality risk. The aggressive nature of this disease sustains an urgent need for more successful, effective drugs. HER-3 - one of the four member of the tyrosin kinase epidermal growth factor receptors (EGFRs) family- is frequently overexpressed in solid tumors, including melanoma...
November 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29217763/improved-tumor-penetration-and-single-cell-targeting-of-antibody-drug-conjugates-increases-anticancer-efficacy-and-host-survival
#7
Cornelius Cilliers, Bruna Menezes, Ian Nessler, Jennifer Linderman, Greg Thurber
Current antibody-drug conjugates (ADC) have made advances in engineering the antibody, linker, conjugation site, small molecule payload and drug-to-antibody ratio (DAR). However, the relationship between heterogeneous intratumoral distribution and efficacy of ADC is poorly understood. Here we compared trastuzumab and ado-trastuzumab emtansine (T-DM1) to study the impact of ADC tumor distribution on efficacy. In a mouse xenograft model insensitive to trastuzumab, co-administration of trastuzumab with a fixed dose of T-DM1 at 3:1 and 8:1 ratios dramatically improved ADC tumor penetration and resulted in twice the improvement in median survival compared to T-DM1 alone...
December 7, 2017: Cancer Research
https://www.readbyqxmd.com/read/29216514/modulation-of-in-vitro-phagocytic-uptake-and-immunogenicity-potential-of-modified-herceptin%C3%A2-conjugated-plga-peg-nanoparticles-for-drug-delivery
#8
Apurva Badkas, Evan Frank, Zilan Zhou, Mina Jafari, Harish Chandra, Vishnu Sriram, Joo-Youp Lee, Jagjit S Yadav
There is an increasing interest in engineered nanoparticle (NP) conjugates for targeted and controlled drug delivery. However, the practical applications of these NP delivery vehicles remain constrained because of their reactivity with the body's immune system defenses resulting in undesirable off-target effects. In this study, poly(D,L lactide-co-glycolide) (PLGA)-b-polyethylene glycol (PEG) NPs conjugated to different quantities of the commercial antibody Herceptin® meant to target HER2-positive breast cancer cells were studied for their immune cell uptake and immunogenic properties (using murine macrophages and human dendritic cells)...
December 4, 2017: Colloids and Surfaces. B, Biointerfaces
https://www.readbyqxmd.com/read/29214842/trastuzumab-emtansine-determining-its-role-in-management-of-her2-breast-cancer
#9
Deborah B Doroshow, Patricia M LoRusso
Trastuzumab emtansine is an antibody-drug conjugate comprised of the anti-HER2 monoclonal antibody trastuzumab linked to DM1 (emtansine), a potent cytotoxic maytansinoid derivative, by a stable linker. This structure results in improved tumor-directed cytotoxicity in HER2+ breast cancer with reduced systemic toxicities, particularly the cardiac toxicities associated with single agent trastuzumab. Phase III trials have demonstrated improved progression-free and overall survival in heavily pretreated patients with advanced HER2+ breast cancer, with an acceptable toxicity profile...
December 7, 2017: Future Oncology
https://www.readbyqxmd.com/read/29213270/nanobodies-and-nanobody-based-human-heavy-chain-antibodies-as-antitumor-therapeutics
#10
REVIEW
Peter Bannas, Julia Hambach, Friedrich Koch-Nolte
Monoclonal antibodies have revolutionized cancer therapy. However, delivery to tumor cells in vivo is hampered by the large size (150 kDa) of conventional antibodies. The minimal target recognition module of a conventional antibody is composed of two non-covalently associated variable domains (VH and VL). The proper orientation of these domains is mediated by their hydrophobic interface and is stabilized by their linkage to disulfide-linked constant domains (CH1 and CL). VH and VL domains can be fused via a genetic linker into a single-chain variable fragment (scFv)...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29211454/latent-warheads-for-targeted-cancer-therapy-design-and-synthesis-of-pro-pyrrolobenzodiazepines-and-conjugates
#11
Iontcho R Vlahov, Longwu Qi, Paul J Kleindl, Hari K Santhapuram, Albert Felten, Garth L Parham, Kevin Wang, Fei You, Jeremy F Vaughn, Spencer J Hahn, Hanna F Klein, Marilynn Vetzel, Joseph A Reddy, Melissa Nelson, Jeff Nicoson, Christopher P Leamon
Pyrrolobenzodiazepines (PBDs) and their dimers (bis-PBDs) have emerged as some of the most potent chemotherapeutic compounds, and are currently under development as novel payloads in antibody-drug conjugates (ADCs). However, when used as stand-alone therapeutics or as warheads for small molecule drug conjugates (SMDCs), dose-limiting toxicities are often observed. As an elegant solution to this inherent problem, we designed diazepine-ring-opened conjugated prodrugs lacking the imine moiety. Once the prodrug (pro-PBD) conjugate enters a targeted cell, cleavage of the linker system triggers the generation of a reactive intermediate possessing an aldehyde and aromatic amine...
December 6, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/29209782/advances-in-immunotherapeutic-research-for-glioma-therapy
#12
REVIEW
Jeremy Tetsuo Miyauchi, Stella E Tsirka
Gliomas are primary malignancies of the brain. Tumors are staged based on malignancy, nuclear atypia, and infiltration of the surrounding brain parenchyma. Tumors are often diagnosed once patients become symptomatic, at which time the lesion is sizable. Glioblastoma (grade IV glioma) is highly aggressive and difficult to treat. Most tumors are diagnosed de novo. The gold standard of therapy, implemented over a decade ago, consists of fractionated radiotherapy and temozolomide, but unfortunately, chemotherapeutic resistance arises...
December 5, 2017: Journal of Neurology
https://www.readbyqxmd.com/read/29206642/measurement-of-sirolimus-concentrations-in-human-blood-using-an-automated-electrochemiluminescence-immunoassay-eclia-a-multicenter-evaluation
#13
Veronique Stove, Pedro Alía Ramos, Pierre Wallemacq, Michael Vogeser, Andre Schuetzenmeister, Christian Schmiedel, Maria Shipkova
BACKGROUND: Therapeutic drug monitoring (TDM) of sirolimus is essential in transplant recipients. We evaluated the performance of a new electrochemiluminescence immunoassay (ECLIA) for measuring sirolimus concentrations in whole blood at five European laboratories. METHODS: Study assessments included repeatability, intermediate precision and functional sensitivity (concentration at coefficient of variation [CV] of 20%) experiments. Method comparisons with liquid chromatography-tandem mass spectrometry (LC-MS/MS; reference method) and two immunoassays (chemiluminescent microparticle immunoassay [CMIA] and antibody-conjugated magnetic immunoassay [ACMIA]) were performed using native samples from patients with kidney transplants...
December 5, 2017: Clinical Chemistry and Laboratory Medicine: CCLM
https://www.readbyqxmd.com/read/29206031/chemoselective-installation-of-amine-bonds-on-proteins-through-aza-michael-ligation
#14
Allyson M Freedy, Maria J Matos, Omar Boutureira, Francisco Corzana, Ana Guerreiro, Padma Akkapeddi, Víctor J Somovilla, Tiago Rodrigues, Karl Nicholls, Bangwen Xie, Gonzalo Jiménez-Osés, Kevin M Brindle, André A Neves, Gonçalo J L Bernardes
Chemical modification of proteins is essential for a variety of important diagnostic and therapeutic applications. Many strategies developed to date lack chemo- and regioselectivity as well as result in non-native linkages that may suffer from instability in vivo and adversely affect the protein's structure and function. We describe here the reaction of N-nucleophiles with the amino acid dehydroalanine (Dha) in a protein context. When Dha is chemically installed in proteins, the addition of a wide-range N-nucleophiles enables the rapid formation of amine linkages (secondary and tertiary) in a chemoselective manner under mild, biocompatible conditions...
December 5, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29200285/site-specific-modification-of-single-chain-antibody-fragments-for-bioconjugation-and-vascular-immunotargeting
#15
Colin Fred Greineder, Carlos H Villa, Landis R Walsh, Raisa Y Kiseleva, Elizabeth D Hood, Makan Khoshnejad, Robert Warden-Rothman, Andrew Tsourkas, Vladimir R Muzykantov
Conjugation of antibodies to drugs and drug carriers improves delivery to target tissues. Widespread implementation and effective translation of this pharmacologic strategy awaits development of affinity ligands capable of a defined degree of modification and highly efficient bioconjugation without loss of affinity. To date, such ligands are lacking for the targeting of therapeutics to vascular endothelial cells. To enable site-specific click chemistry conjugation to therapeutic cargo, we used the bacterial transpeptidase, sortase A, to attach short azidolysine containing peptides to three endothelial-specific single chain antibody fragments (scFv)...
December 4, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/29196412/a-phase-1-trial-of-vadastuximab-talirine-as-monotherapy-in-patients-with-cd33-positive-acute-myeloid-leukemia-aml
#16
Eytan M Stein, Roland B Walter, Harry P Erba, Amir T Fathi, Anjali S Advani, Jeffrey E Lancet, Farhad Ravandi, Tibor Kovacsovics, Daniel J DeAngelo, Dale Bixby, Stefan Faderl, Anand P Jillella, Phoenix Ho, Megan M O'Meara, Baiteng Zhao, Charles Biddle-Snead, Anthony S Stein
Vadastuximab talirine (SGN-CD33A, 33A) is an antibody-drug conjugate consisting of pyrrolobenzodiazepine dimers linked to a monoclonal antibody targeting CD33, which is expressed in the majority of acute myeloid leukemia (AML) patients. This phase 1 study (clinicaltrials.gov NCT01902329) evaluated the safety, pharmacokinetics, and preliminary activity of vadastuximab talirine and determined the recommended monotherapy dose in patients with relapsed or refractory AML. Additional expansion cohorts tested vadastuximab talirine in specific subpopulations of relapsed AML, and in a cohort of older, treatment-naïve patients...
December 1, 2017: Blood
https://www.readbyqxmd.com/read/29194581/hodgkin-lymphoma-a-review-and-update-on-recent-progress
#17
REVIEW
Satish Shanbhag, Richard F Ambinder
Hodgkin lymphoma (HL) is a unique hematopoietic neoplasm characterized by cancerous Reed-Sternberg cells in an inflammatory background. Patients are commonly diagnosed with HL in their 20s and 30s, and they present with supradiaphragmatic lymphadenopathy, often with systemic B symptoms. Even in advanced-stage disease, HL is highly curable with combination chemotherapy, radiation, or combined-modality treatment. Although the same doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapeutic regimen has been the mainstay of therapy over the last 30 years, risk-adapted approaches have helped de-escalate therapy in low-risk patients while intensifying treatment for higher risk patients...
December 1, 2017: CA: a Cancer Journal for Clinicians
https://www.readbyqxmd.com/read/29193956/native-ms-analysis-of-monoclonal-antibody-conjugates-by-fourier-transform-ion-cyclotron-resonance-mass-spectrometry
#18
Iain David Grant Campuzano, Chawita Netirojjanakul, Michael Nshanian, Jennifer L Lippens, David Peter Alexander Kilgour, Steven L Van Orden, Joseph Loo
Antibody drug conjugates (ADCs) are an important class of therapeutic molecule currently being used to treat HER2-positive metastatic breast cancer, relapsed or refractory Hodgkin lymphoma, and systemic anaplastic large cell lymphoma. An ADC typically consists of a small molecule or peptide-based cytotoxic moiety covalently linked, via lysine or cysteine residues, to a monoclonal antibody (mAb) scaffold. Mass spectrometric (MS) characterization of these molecules afford highly accurate molecular weight (MW) and drug-to-antibody ratio (DAR) determination, and is typically performed using orthogonal acceleration time-of-flight (oa-ToF) analysers and more recently Orbitrap instruments...
December 1, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/29192287/next-generation-antibody-drugs-pursuit-of-the-high-hanging-fruit
#19
REVIEW
Paul J Carter, Greg A Lazar
Antibodies are the most rapidly growing drug class and have a major impact on human health, particularly in oncology, autoimmunity and chronic inflammatory diseases. Many of the best understood and most tractable cell surface and secreted targets with known roles in human diseases have been extensively exploited for antibody drug development. In this Review, we focus on emerging and novel mechanisms of action of antibodies and innovative targeting strategies that could extend their therapeutic applications, including antibody-drug conjugates, bispecific antibodies and antibody engineering to facilitate more effective delivery...
December 1, 2017: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/29189429/new-developments-in-immunotherapy-for-pediatric-solid-tumors
#20
Liora M Schultz, Robbie Majzner, Kara L Davis, Crystal Mackall
PURPOSE OF REVIEW: Building upon preclinical advances, we are uncovering immunotherapy strategies that are translating into improved outcomes in tumor subsets. Advanced pediatric solid tumors carry poor prognoses and resultant robust efforts to apply immunotherapy advances to pediatric solid tumors are in progress. Here, we discuss recent developments in the field using mAb and mAb-based therapies including checkpoint blockade and chimeric antigen receptors (CARs). RECENT FINDINGS: The pediatric solid tumor mAb experience targeting the diganglioside, GD2, for patients with neuroblastoma has been the most compelling to date...
November 20, 2017: Current Opinion in Pediatrics
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