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https://www.readbyqxmd.com/read/29784748/emerging-treatment-options-for-acute-lymphoblastic-leukemia-focus-on-car-t-cell-therapy
#1
Patrick A Brown, Bijal Shah
Acute lymphoblastic leukemia (ALL) comprises a heterogeneous group of diseases with different morphologic, cytogenetic, and molecular subgroups, some of which have significant therapeutic implications. It typically presents with an aggressive clinical course, and among adults, responds poorly to standard chemotherapy, and carries a high risk for relapse. Despite the significant progress made in inducing remission, frequent relapses remain a challenge. Novel drugs, such as potent later-generation tyrosine kinase inhibitors, antibody-drug conjugates, bispecific monoclonal antibodies, and chimeric antigen receptor (CAR) T-cell therapies, are being investigated in patients with ALL...
May 2018: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/29771629/brain-uptake-of-multivalent-and-multi-specific-dvd-ig-proteins-after-systemic-administration
#2
Denise Karaoglu Hanzatian, Annette Schwartz, Farid Gizatullin, Jamie Erickson, Kangwen Deng, Ruth Villanueva, Christopher Stedman, Cristina Harris, Tariq Ghayur, Andrew Goodearl
Therapeutic monoclonal antibodies and endogenous IgG antibodies show limited uptake into the central nervous system (CNS) due to the blood-brain barrier (BBB), which regulates and controls the selective and specific transport of both exogenous and endogenous materials to the brain. The use of natural transport mechanisms, such as receptor-mediated transcytosis (RMT), to deliver antibody therapeutics into the brain have been studied in rodents and monkeys. Recent successful examples include monovalent bispecific antibodies and mono- or bivalent fusion proteins; however, these formats do not have the capability to bind to both the CNS target and the BBB transport receptor in a bivalent fashion as a canonical antibody would...
May 17, 2018: MAbs
https://www.readbyqxmd.com/read/29764159/emerging-role-of-immunotherapy-for-childhood-cancers
#3
Rupert Handgretinger, Patrick Schlegel
Recent developments in cell and gene therapy have a great impact on the new therapeutic approaches in pediatric cancers. Monoclonal antibodies for neuroblastoma and bispecific antibodies for leukemia have induced significant clinical responses for otherwise chemorefractory patients. Moreover, cellular therapeutic approaches including chimeric antigen receptor (CAR) T-cells as well as natural killer (NK) cells have the potential to cure patients with so far incurable malignancies and are the basis for future new therapies for pediatric cancer...
April 2018: Chinese Clinical Oncology
https://www.readbyqxmd.com/read/29763554/template-catalyzed-disulfide-conjugation-of-monoclonal-antibodies-using-a-natural-amino-acid-tag
#4
Jeremy D King, Yuelong Ma, Yi-Chui Kuo, Krzysztof P Bzymek, Leah H Goodstein, Kassondra Meyer, Roger E Moore, Desiree Crow, David Colcher, Gagandeep Singh, David A Horne, John C Williams
The high specificity and favorable pharmacological properties of monoclonal antibodies (mAbs) have prompted significant interest in re-engineering this class of molecules to add novel functionalities for enhanced therapeutic and diagnostic potential. Here, we used the high affinity, meditope-Fab interaction to template and drive the rapid, efficient, and stable site-specific formation of a disulfide bond. We demonstrate that this template-catalyzed strategy provides a consistent and reproducible means to conjugate fluorescent dyes, cytotoxins, or "click" chemistry handles to meditope-enabled mAbs (memAbs) and memFabs...
May 15, 2018: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/29754509/-new-and-traditional-directions-in-the-biology-and-management-of-childhood-acute-lymphoblastic-leukemia
#5
Bálint Egyed, Gábor Kovács, Nóra Kutszegi, Andrea Rzepiel, Judit Csányiné Sági, Dániel János Erdélyi, Judit Müller, Ágnes Félné Semsei
Owing to clinical trials and improvement over the past few decades, the majority of children with acute lymphoblastic leukemia (ALL) survive by first-line chemotherapy and combat with the problems of returning to community. However, many patients may have severe acute or late therapeutic side effects, and the survival rate in some groups (e.g., patients with MLL rearrangements, hypodiploidy, IKZF1 mutation or early precursor T cell phenotype) is far behind the average. Innovative strategies in medical attendance provide better clinical outcomes for them: complete gene diagnostics, molecularly targeted anticancer treatment, immuno-oncology and immune cell therapy...
May 2018: Orvosi Hetilap
https://www.readbyqxmd.com/read/29742077/philadelphia-chromosome-positive-acute-lymphoblastic-leukemia-in-adults-current-treatments-and-future-perspectives
#6
Musa Yilmaz, Hagop Kantarjian, Farhad Ravandi-Kashani, Nicholas J Short, Elias Jabbour
Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) accounts for approximately one-fourth of cases of adult ALL. It typically presents with an aggressive clinical course, responds poorly to standard chemotherapy, and carries a high risk for relapse. The landscape of Ph+ ALL therapy has changed favorably since the development of tyrosine kinase inhibitors (TKIs). With the successful incorporation of TKIs into chemotherapy regimens, remissions occur more frequently and patients live longer...
March 2018: Clinical Advances in Hematology & Oncology: H&O
https://www.readbyqxmd.com/read/29734520/routine-measurements-of-factor-viii-activity-and-inhibitor-titer-in-the-presence-of-emicizumab-utilizing-anti-idiotype-monoclonal-antibodies
#7
Keiji Nogami, Tetsuhiro Soeda, Tomoko Matsumoto, Yoshiki Kawabe, Takehisa Kitazawa, Midori Shima
BACKGROUND: Emicizumab is an anti-factor (F)IXa/X bispecific monoclonal antibody (mAb), mimicking the Factor (F)VIIIa cofactor activity. Emicizumab does not require activation by thrombin and its shortening effect on the activated partial prothrombin time (aPTT) is more pronounced than that of Factor (F)VIII. aPTT-based FVIII activity (FVIII:C) and FVIII inhibiter titer measurements are influenced by the presence of emicizumab. AIM: To establish a reliable aPTT-based assay to measure FVIII in the presence of emicizumab...
May 7, 2018: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/29728897/translational-pk-pd-modeling-analysis-of-mcla-128-a-her2-her3-bispecific-monoclonal-antibody-to-predict-clinical-efficacious-exposure-and-dose
#8
Aurelia H M de Vries Schultink, Robert P Doornbos, Alexander B H Bakker, Kees Bol, Mark Throsby, Cecile Geuijen, David Maussang, Jan H M Schellens, Jos H Beijnen, Alwin D R Huitema
Introduction MCLA-128 is a bispecific monoclonal antibody targeting the HER2 and HER3 receptors. Pharmacokinetics (PK) and pharmacodynamics (PD) of MCLA-128 have been evaluated in preclinical studies in cynomolgus monkeys and mice. The aim of this study was to characterize the PK and PD of MCLA-128 and to predict a safe starting dose and efficacious clinical dose for the First-In-Human study. Methods A PK-PD model was developed based on PK data from cynomolgus monkeys and tumor growth data from a mouse JIMT-1 xenograft model...
May 5, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29725336/tribody-her2-2-xcd16-is-more-effective-than-trastuzumab-in-enhancing-%C3%AE-%C3%AE-t-cell-and-natural-killer-cell-cytotoxicity-against-her2-expressing-cancer-cells
#9
Hans H Oberg, Christian Kellner, Daniel Gonnermann, Susanne Sebens, Dirk Bauerschlag, Martin Gramatzki, Dieter Kabelitz, Matthias Peipp, Daniela Wesch
An enhanced expression of human epidermal growth factor receptor 2 (HER2, ErbB2) often occurs in an advanced stage of breast, ovarian, gastric or esophageal cancer, and pancreatic ductal adenocarcinoma (PDAC). Commonly, HER2 expression is associated with poor clinical outcome or chemoresistance in ovarian and breast cancer patients. Treatment with humanized anti-HER2 monoclonal antibodies, such as trastuzumab or pertuzumab, has improved the outcome of patients with HER2-positive metastatic gastric or breast cancer, but not all patients benefit...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29718394/generation-of-orthogonal-fab-based-trispecific-antibody-formats
#10
Xiufeng Wu, Richard Yuan, Michael Bacica, Stephen J Demarest
The clinical success of monoclonal antibodies to treat diseases across nearly every therapeutic area has spurred advances in bispecific antibody technology with the goal of cost-effectively combining various therapies or providing novel mechanisms for disease intervention. Many novel bispecific antibodies are now in clinical development or the late pre-clinical setting. A new horizon exists for novel molecular entities with the ability to bind three or more antigens. Here we describe the production and characterization of novel trispecific antibody-like proteins denoted 'OrthoTsAbs' that self-assemble through the application of engineered antibody domain interfaces...
April 28, 2018: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/29713210/inotuzumab-ozogamicin-in-the-treatment-of-relapsed-refractory-acute-b-cell-lymphoblastic-leukemia
#11
REVIEW
Natalie Uy, Michelle Nadeau, Maximilian Stahl, Amer M Zeidan
The improvement in outcomes of adult patients with acute lymphoblastic leukemia (ALL) has been modest, with the exception of Philadelphia chromosome-positive disease, despite advances in supportive care and stem cell transplantation. The recent approvals of novel agents, including the bispecific T-cell engager blinatumomab, the antibody-drug conjugate inotuzumab ozogamicin, and chimeric antigen receptor T-cell products are changing the management of B-ALL, which traditionally relied on chemotherapy-based approaches...
2018: Journal of Blood Medicine
https://www.readbyqxmd.com/read/29685337/evaluation-of-recent-protein-a-stationary-phase-innovations-for-capture-of-biotherapeutics
#12
Timothy M Pabst, Johnny Thai, Alan K Hunter
We describe a comprehensive evaluation of 12 Protein A stationary phases for capture of biotherapeutics. We first examine the morphological properties of the stationary phases using a variety of orthogonal techniques including electron microscopy, particle sizing, pressure-flow behavior, and isocratic pulse response. A panel of nine proteins spanning a wide range of structures and biochemical properties was then used to assess equilibrium uptake, mass transport, dynamic binding capacity, and elution pH. Process performance and product quality were also examined under realistic bioprocess conditions using clarified mammalian cell culture broth...
April 7, 2018: Journal of Chromatography. A
https://www.readbyqxmd.com/read/29684909/hyphenation-of-size-exclusion-chromatography-to-native-ion-mobility-mass-spectrometry-for-the-analytical-characterization-of-therapeutic-antibodies-and-related-products
#13
Anthony Ehkirch, Oscar Hernandez-Alba, Olivier Colas, Alain Beck, Davy Guillarme, Sarah Cianférani
Mass spectrometry performed in non-denaturing conditions (native MS), and its hyphenation to ion mobility spectrometry (IM-MS), have gained interest for the qualitative and quantitative characterization of intact monoclonal antibody-related (mAb) products. However, one main drawback is the manual sample preparation, which hampers its routine use in high throughput automated environments. Size exclusion chromatography (SEC) appears as an interesting technique to perform online buffer exchange in an automated way...
April 12, 2018: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/29672587/functional-relevance-of-in-vivo-half-antibody-exchange-of-an-igg4-therapeutic-antibody-drug-conjugate
#14
Peter Herbener, Kurt Schönfeld, Martin König, Matthias Germer, Jude M Przyborski, Katrin Bernöster, Jörg Schüttrumpf
An increasing number of monoclonal antibodies and derivatives such as antibody-drug conjugates (ADC) are of the IgG1 and IgG4 isotype with distinct structural and functional properties. In cases where antibody-mediated cytotoxicity is not desired, IgG4 is often used, as its Fc region is relatively poor at inducing antibody-dependent cell-mediated or complement-dependent cytotoxicity. IgG4 ADCs with highly cytotoxic drugs against proliferating target cells but which lack or have diminished antibody effector functions against quiescent cells may have a favorable safety profile compared to IgG1...
2018: PloS One
https://www.readbyqxmd.com/read/29670611/advances-in-biomarker-guided-therapy-for-pediatric-and-adult-onset-neuroinflammatory-disorders-targeting-chemokines-cytokines
#15
REVIEW
Michael R Pranzatelli
The concept and recognized components of "neuroinflammation" are expanding at the intersection of neurobiology and immunobiology. Chemokines (CKs), no longer merely necessary for immune cell trafficking and positioning, have multiple physiologic, developmental, and modulatory functionalities in the central nervous system (CNS) through neuron-glia interactions and other mechanisms affecting neurotransmission. They issue the "help me" cry of neurons and astrocytes in response to CNS injury, engaging invading lymphoid cells (T cells and B cells) and myeloid cells (dendritic cells, monocytes, and neutrophils) (adaptive immunity), as well as microglia and macrophages (innate immunity), in a cascade of events, some beneficial (reparative), others destructive (excitotoxic)...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29595951/amplification-of-cd20-crosslinking-in-rituximab-resistant-b-lymphoma-cells-enhances-apoptosis-induction-by-drug-free-macromolecular-therapeutics
#16
Lian Li, Jiyuan Yang, Jiawei Wang, Jindrich Kopecek
Although the CD20-targeted monoclonal antibody rituximab (RTX) has revolutionized the therapeutic landscape for B-cell malignancy, relapsed and refractory disease due to RTX resistance continue to constitute major challenges, illustrating the need for better therapies. Here, we apply drug-free macromolecular therapeutics (DFMT) that amplifies CD20 crosslinking to enhance apoptosis in RTX resistant cells. Bispecific engager (anti-CD20 Fab' conjugated with oligonucleotide1) pretargets CD20 and the deletion of Fc-region minimizes its premature endocytosis in resistant cells that rapidly internalize and consume CD20/RTX complexes...
March 29, 2018: ACS Nano
https://www.readbyqxmd.com/read/29528990/nkg2d-immunoligand-rg7s-mica-enhances-nk-cell-mediated-immunosurveillance-in-colorectal-carcinoma
#17
Tong Wang, Fumou Sun, Yang Wang, Jiahao Jiang, Mingzhu Pan, Minne Yuan, Hang Zhang, Xiaodian Du, Kamal Hezam, Kai Song, Min Wang, Juan Zhang
Colorectal carcinoma (CRC) is one of the most common malignant cancers worldwide. The poor response of CRC to chemotherapy has whipped up the interest in targeted therapy with monoclonal antibodies for its potential efficiency. However, cetuximab, as one of the first-line targeted drugs in the treatment of CRC, has drug resistance and poor prognosis in clinic. To address this, a novel bispecific protein with CRC targeting and natural killer (NK) cell triggering was used for treatment. NK cell-mediated immunosurveillance is normally activated by the activating receptor natural killer cell receptor NK group 2, member D (NKG2D), which binds its key ligand major histocompatibility complex (MHC) class I-related chain A (MICA) expressed on the tumor cells...
April 2018: Journal of Immunotherapy
https://www.readbyqxmd.com/read/29500195/design-and-evaluation-of-bi-and-trispecific-antibodies-targeting-multiple-filovirus-glycoproteins
#18
Elisabeth K Nyakatura, Samantha E Zak, Anna Z Wec, Daniel Hofmann, Sergey Shulenin, Russell R Bakken, M Javad Aman, Kartik Chandran, John M Dye, Jonathan R Lai
Filoviruses (family Filoviridae) include five ebolaviruses and Marburg virus. These pathogens cause a rapidly progressing and severe viral disease with high mortality rates (generally 30-90%). Outbreaks of filovirus disease are sporadic and, until recently, were limited to less than 500 cases. However, the 2013-2016 epidemic in western Africa, caused by Ebola virus (EBOV), illustrated the potential of filovirus outbreaks to escalate to a much larger scale (over 28,000 suspected cases). mAbs against the envelope glycoprotein represent a promising therapeutic platform for managing filovirus infections...
April 20, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29490423/crystal-structure-of-b-cell-co-receptor-cd19-in-complex-with-antibody-b43-reveals-an-unexpected-fold
#19
Alexey Teplyakov, Galina Obmolova, Jinquan Luo, Gary L Gilliland
CD19 is a transmembrane protein expressed on malignant B cells, but not in other lineages or other tissues, which makes it an attractive target for monoclonal antibody-mediated immunotherapy. Anti-CD19 antibody B43 was utilized in a bispecific T-cell engager (BiTE) blinatumomab that demonstrated potency for the treatment of relapsed acute lymphoblastic leukemia. To gain insight into the mechanism of action of the antibody, the crystal structure of B43 Fab was determined in complex with CD19 and in the unbound form...
May 2018: Proteins
https://www.readbyqxmd.com/read/29482895/bispecific-antibody-based-therapeutics-strengths-and-challenges
#20
REVIEW
Archana Thakur, Manley Huang, Lawrence G Lum
Monoclonal antibody-based targeted therapy has greatly improved treatment options for patients. However, long-term efficacy of such antibodies is limited by resistance mechanisms. New insights into the mechanisms by which tumors evade immune control have driven innovative therapeutic strategies to eliminate cancer by re-directing immune cells to tumors. Advances in protein engineering technology have generated multiple bispecific antibody (BsAb) formats capable of targeting multiple antigens as a single agent...
February 20, 2018: Blood Reviews
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