Hampig Raphael Kourie, Gil Awada, Ahmad Hussein Awada
2015 was marked by the tsunami of immune checkpoint inhibitors revealed by numerous FDA approvals, publications and abstracts in relation with these drugs in different cancers and settings. First, we reported all new indications of anti-CTLA4 and anti-PD1 approved by the FDA, the positive clinical trials published and the abstracts with promising results at important scientific meetings during 2015. Then, we discussed different critical issues of these new agents going from their predictive factors, combination therapies, tumor response patterns, efficacy in particular settings, side effect management to cost and economic burden...
May 2016: Critical Reviews in Oncology/hematology
Flora Peyvandi, Marie Scully, Johanna A Kremer Hovinga, Spero Cataland, Paul Knöbl, Haifeng Wu, Andrea Artoni, John-Paul Westwood, Magnus Mansouri Taleghani, Bernd Jilma, Filip Callewaert, Hans Ulrichts, Christian Duby, Dominique Tersago
BACKGROUND: Acquired thrombotic thrombocytopenic purpura (TTP) is caused by aggregation of platelets on ultralarge von Willebrand factor multimers. This microvascular thrombosis causes multiorgan ischemia with potentially life-threatening complications. Daily plasma exchange and immunosuppressive therapies induce remission, but mortality and morbidity due to microthrombosis remain high. METHODS: Caplacizumab, an anti-von Willebrand factor humanized single-variable-domain immunoglobulin (Nanobody), inhibits the interaction between ultralarge von Willebrand factor multimers and platelets...
February 11, 2016: New England Journal of Medicine
Sagar Lonial, Meletios Dimopoulos, Antonio Palumbo, Darrell White, Sebastian Grosicki, Ivan Spicka, Adam Walter-Croneck, Philippe Moreau, Maria-Victoria Mateos, Hila Magen, Andrew Belch, Donna Reece, Meral Beksac, Andrew Spencer, Heather Oakervee, Robert Z Orlowski, Masafumi Taniwaki, Christoph Röllig, Hermann Einsele, Ka Lung Wu, Anil Singhal, Jesus San-Miguel, Morio Matsumoto, Jessica Katz, Eric Bleickardt, Valerie Poulart, Kenneth C Anderson, Paul Richardson
BACKGROUND: Elotuzumab, an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7), showed activity in combination with lenalidomide and dexamethasone in a phase 1b-2 study in patients with relapsed or refractory multiple myeloma. METHODS: In this phase 3 study, we randomly assigned patients to receive either elotuzumab plus lenalidomide and dexamethasone (elotuzumab group) or lenalidomide and dexamethasone alone (control group)...
August 13, 2015: New England Journal of Medicine
Tomas Kalincik, Dana Horakova, Tim Spelman, Vilija Jokubaitis, Maria Trojano, Alessandra Lugaresi, Guillermo Izquierdo, Csilla Rozsa, Pierre Grammond, Raed Alroughani, Pierre Duquette, Marc Girard, Eugenio Pucci, Jeannette Lechner-Scott, Mark Slee, Ricardo Fernandez-Bolanos, Francois Grand'Maison, Raymond Hupperts, Freek Verheul, Suzanne Hodgkinson, Celia Oreja-Guevara, Daniele Spitaleri, Michael Barnett, Murat Terzi, Roberto Bergamaschi, Pamela McCombe, Jose Sanchez-Menoyo, Magdolna Simo, Tunde Csepany, Gabor Rum, Cavit Boz, Eva Havrdova, Helmut Butzkueven
OBJECTIVE: In patients suffering multiple sclerosis activity despite treatment with interferon β or glatiramer acetate, clinicians often switch therapy to either natalizumab or fingolimod. However, no studies have directly compared the outcomes of switching to either of these agents. METHODS: Using MSBase, a large international, observational, prospectively acquired cohort study, we identified patients with relapsing-remitting multiple sclerosis experiencing relapses or disability progression within the 6 months immediately preceding switch to either natalizumab or fingolimod...
March 2015: Annals of Neurology
Marisa Fernandes das Neves, Susana Oliveira, Marta C Amaral, José Delgado Alves
No abstract text is available yet for this article.
February 2015: Rheumatology
Adriana H Tremoulet, Sonia Jain, Preeti Jaggi, Susan Jimenez-Fernandez, Joan M Pancheri, Xiaoying Sun, John T Kanegaye, John P Kovalchin, Beth F Printz, Octavio Ramilo, Jane C Burns
BACKGROUND: Kawasaki disease, the most common cause of acquired heart disease in developed countries, is a self-limited vasculitis that is treated with high doses of intravenous immunoglobulin. Resistance to intravenous immunoglobulin in Kawasaki disease increases the risk of coronary artery aneurysms. We assessed whether the addition of infliximab to standard therapy (intravenous immunoglobulin and aspirin) in acute Kawasaki disease reduces the rate of treatment resistance. METHODS: We undertook a phase 3, randomised, double-blind, placebo-controlled trial in two children's hospitals in the USA to assess the addition of infliximab (5 mg per kg) to standard therapy...
May 17, 2014: Lancet
Jun-ichi Nishimura, Masaki Yamamoto, Shin Hayashi, Kazuma Ohyashiki, Kiyoshi Ando, Andres L Brodsky, Hideyoshi Noji, Kunio Kitamura, Tetsuya Eto, Toru Takahashi, Masayoshi Masuko, Takuro Matsumoto, Yuji Wano, Tsutomu Shichishima, Hirohiko Shibayama, Masakazu Hase, Lan Li, Krista Johnson, Alberto Lazarowski, Paul Tamburini, Johji Inazawa, Taroh Kinoshita, Yuzuru Kanakura
BACKGROUND: Eculizumab is a humanized monoclonal antibody that targets complement protein C5 and inhibits terminal complement-mediated hemolysis associated with paroxysmal nocturnal hemoglobinuria (PNH). The molecular basis for the poor response to eculizumab in a small population of Japanese patients is unclear. METHODS: We assessed the sequences of the gene encoding C5 in patients with PNH who had either a good or poor response to eculizumab. We also evaluated the functional properties of C5 as it was encoded in these patients...
February 13, 2014: New England Journal of Medicine
David C Smith, Peter D Eisenberg, Georgy Manikhas, Rashmi Chugh, Matthew A Gubens, Robert J Stagg, Ann M Kapoun, Lu Xu, Jakob Dupont, Branimir Sikic
PURPOSE: This phase I trial evaluated the safety, pharmacokinetics, and pharmacodynamics of demcizumab (OMP-21M18), a humanized IgG2 mAb targeting the Notch ligand DLL4 in adult patients with advanced malignancies. EXPERIMENTAL DESIGN: Standard 3+3 design, with demcizumab 0.5, 1, 2.5, or 5 mg/kg weekly or 2.5, 5, or 10 mg/kg every other week, with an expansion cohort at 10 mg/kg every other week. Dose-limiting toxicities (DLT) were assessed during the first 28 days...
December 15, 2014: Clinical Cancer Research
Edward A Clark
This perspective traces developments using monoclonal antibody technology that led to the discovery of CD40, a receptor that on B cells mediates "T cell help" and on dendritic cells helps to program CD8 T cell responses. I discuss some things that we got right during the path of discovery and some things we missed. Immunotherapies that block or stimulate the CD40 pathway hold great promise for treatment of autoimmune diseases and cancers.
2014: Frontiers in Immunology
(no author information available yet)
The Folfiri protocol is often proposed to patients with metastatic colorectal cancer in relapse or treatment failure after the Folfox protocol. The benefit of adding a monoclonal antibody is far from certain. In two trials, addition of bevacizumab, a VEGF inhibitor, to a second-line regimen prolonged survival by about two months, at a cost of many additional serious or even life-threatening adverse effects. Aflibercept (Zaltrap, Sanofi Aventis), another VEGF inhibitor, has been authorised in the European Union as an adjunct to the Folfiri protocol in patients with metastatic colorectal cancer in treatment failure or relapse after a first-line regimen including oxaliplatin (Folfox protocol, for example)...
September 2014: Prescrire International
Nripendra Nath Mishra, Shakir Ali, Praveen K Shukla
Candida albicans is an opportunistic dimorphic pathogen that exists in both planktonic and biofilm phases causing deep-rooted infections in mainly immunocompromised patients. Antibodies are believed to play anti-Candida activity by different mechanisms, like inhibition of adhesion and neutralization of virulence-related antigens. Inhibition of adhesion is one of the important strategies to prevent Candida infections and biofilm formation. In this study, monoclonal antibody (MAb 7D7) against C. albicans biofilm cell surface antigen (47...
January 2015: World Journal of Microbiology & Biotechnology
Xiangnan Du, Benjamin C Lin, Qian-Rena Wang, Hao Li, Ellen Ingalla, Janet Tien, Isabelle Rooney, Avi Ashkenazi, Elicia Penuel, Jing Qing
PURPOSE: The aim of this study was to identify noninvasive pharmacodynamic biomarkers of FGFR3-targeted therapies in bladder cancer to facilitate the clinical development of experimental agent targeting FGFR3. EXPERIMENTAL DESIGN: Potential soluble pharmacodynamic biomarkers of FGFR3 were identified using a combination of transcriptional profiling and biochemical analyses in preclinical models. Two matrix metalloproteinases (MMP), MMP-1 and MMP-10, were selected for further studies in human bladder cancer xenograft models treated with a specific anti-FGFR3 monoclonal antibody, R3Mab...
December 15, 2014: Clinical Cancer Research
Mark Butt, Mark Evans, Christopher J Bowman, Thomas Cummings, Satoru Oneda, David Shelton, Mark Zorbas
Tanezumab, an antibody to nerve growth factor, was administered to pregnant cynomolgus monkeys at 0, 0.5, 4, and 30 mg/kg weekly, beginning gestation day (GD) 20 through parturition (∼GD165). Maternal tanezumab administration appeared to increase stillbirths and infant mortality, but no consistent pattern of gross and/or microscopic change was detected to explain the mortality. Offspring exposed in utero were evaluated at 12 months of age using light microscopy (all tissues), stereology (basal forebrain cholinergic and dorsal root ganglia neurons), and morphometry (sural nerve)...
December 2014: Toxicological Sciences: An Official Journal of the Society of Toxicology
Pauline A van Schouwenburg, Simone Kruithof, Christian Votsmeier, Karin van Schie, Margreet H Hart, Rob N de Jong, Esther E L van Buren, Marieke van Ham, Lucien Aarden, Gertjan Wolbink, Diana Wouters, Theo Rispens
The production of antibodies to adalimumab in autoimmune patients treated with adalimumab is shown to diminish treatment efficacy. We previously showed that these antibodies are almost exclusively neutralizing, indicating a restricted response. Here, we investigated the characteristics of a panel of patient-derived monoclonal antibodies for binding to adalimumab. Single B-cells were isolated from two patients, cultured, and screened for adalimumab specificity. Analysis of variable region sequences of 16 clones suggests that the immune response against adalimumab is broad, involving multiple B-cell clones each using different combinations of V(D)J segments...
December 12, 2014: Journal of Biological Chemistry
Nicholas Schwab, Tilman Schneider-Hohendorf, Heinz Wiendl
Multiple sclerosis (MS) is a disorder of putative autoimmune origin, where immune cells invade the central nervous system and cause damage by attacking the myelin sheath of nerve cells. The blockade of the integrin very late antigen-4 (VLA-4) with the monoclonal antibody natalizumab has become the most effective therapy against MS since its approval in 2004. It is assumed that the inhibition of VLA-4-mediated immune cell adhesion to the endothelium of the blood-brain barrier (BBB) alleviates pathogenic processes of MS and, therefore, reduces disease severity and burden...
January 2015: International Immunology
Paolo A Ascierto, Raffaele Addeo, Giacomo Cartenì, Bruno Daniele, Michele De Laurentis, Giovanni Pietro Ianniello, Alessandro Morabito, Giovannella Palmieri, Stefano Pepe, Francesco Perrone, Sandro Pignata, Vincenzo Montesarchio
The therapeutic approach to advanced or metastatic solid tumors, either with chemotherapy or targeted therapies, is mainly palliative. Resistance to chemotherapy occurs very frequently and is one of the most important reasons for disease progression. Immunotherapy has the potential to mount an ongoing, dynamic immune response that can kill tumor cells for an extended time after the conventional therapy has been administered. Such a long-lasting response is potentially able to completely eradicate tumor cells, rather than producing only a temporary killing of cells...
October 21, 2014: Journal of Translational Medicine
Raewyn M Poole
Pembrolizumab [Keytruda(®) (US)], a humanized monoclonal antibody against the programmed death receptor-1 (PD-1) protein, has been developed by Merck & Co for the treatment of cancer. Pembrolizumab has received its first global approval for the treatment of advanced, unresectable or metastatic malignant melanoma in the US, for use in patients with disease progression after prior treatment with ipilimumab and, for BRAF V600 mutation-positive patients, a BRAF inhibitor. It is the first anti-PD-1 therapy to receive regulatory approval in the US, and is currently under regulatory review in the EU...
October 2014: Drugs
Priscilla Y Hsue, Rebecca Scherzer, Carl Grunfeld, John Imboden, Yuaner Wu, Gus Del Puerto, Elaine Nitta, Judy Shigenaga, Amanda Schnell Heringer, Peter Ganz, Jonathan Graf
BACKGROUND: Individuals with rheumatoid arthritis (RA) are at increased risk for cardiovascular disease, partly due to systemic inflammation and endothelial dysfunction. B-cells play an important pathogenic role in the inflammatory process that drives RA disease activity. Rituximab, a chimeric murine/human monoclonal antibody that depletes B-cells, is an effective therapy for RA. The purpose of this study was to determine whether B-cell depletion with rituximab reduces systemic inflammation and improves macrovascular (brachial artery flow-mediated dilation, FMD) and microvascular (reactive hyperemia) endothelial function in RA patients...
October 21, 2014: Journal of the American Heart Association
Nicholas G Kounis, George D Soufras, Grigorios Tsigkas, George Hahalis
Monoclonal antibodies are currently used in the treatment of neoplastic, hematological, or inflammatory diseases, a practice that is occasionally associated with a variety of systemic and cutaneous adverse events. Cardiac adverse events include cardiomyopathy, ventricular dysfunction, arrhythmias, arrests, and acute coronary syndromes, such as acute myocardial infarction and vasospastic angina pectoris. These events generally follow hypersensitivity reactions including cutaneous erythema, pruritus chills, and precordial pain...
2014: Oncoimmunology
Jonathan Q Tran, Jitesh Rana, Frederik Barkhof, Isaac Melamed, Hakop Gevorkyan, Mike P Wattjes, Remko de Jong, Kristin Brosofsky, Soma Ray, Lei Xu, Jim Zhao, Edward Parr, Diego Cadavid
OBJECTIVE: To evaluate the safety, tolerability, and pharmacokinetics (PK) of BIIB033 (anti-LINGO-1 monoclonal antibody) in healthy volunteers and participants with multiple sclerosis (MS). METHODS: In 2 separate randomized, placebo-controlled studies, single ascending doses (SAD; 0.1-100 mg/kg) of BIIB033 or placebo were administered via IV infusion or subcutaneous injection to 72 healthy volunteers, and multiple ascending doses (MAD; 0.3-100 mg/kg; 2 doses separated by 14 days) of BIIB033 or placebo were administered via IV infusion to 47 participants with relapsing-remitting or secondary progressive MS...
August 2014: Neurology® Neuroimmunology & Neuroinflammation
2014-11-11 15:21:38
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