Marina Roell
University of California, Berkeley
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Featured researches published by Marina Roell.
mAbs | 2011
Alexander Owyang; Hassan Issafras; John A. Corbin; Kiran Ahluwalia; Paul Larsen; Elizabeth Pongo; Masahisa Handa; Arnold Horwitz; Marina Roell; Mary Haak-Frendscho; Linda Masat
Interleukin-1β (IL-1β) is a potent mediator of inflammatory responses and plays a role in the differentiation of a number of lymphoid cells. In several inflammatory and autoimmune diseases, serum levels of IL-1β are elevated and correlate with disease development and severity. The central role of the IL-1 pathway in several diseases has been validated by inhibitors currently in clinical development or approved by the FDA. However, the need to effectively modulate IL-1β-mediated local inflammation with the systemic delivery of an efficacious, safe and convenient drug still exists. To meet these challenges, we developed XOMA 052 (gevokizumab), a potent anti-IL-1β neutralizing antibody that was designed in silico and humanized using Human Engineering™ technology. XOMA 052 has a 300 femtomolar binding affinity for human IL-1β and an in vitro potency in the low picomolar range. XOMA 052 binds to a unique IL-1β epitope where residues critical for binding have been identified. We have previously reported that XOMA 052 is efficacious in vivo in a diet-induced obesity mouse model thought to be driven by low levels of chronic inflammation. We report here that XOMA 052 also reduces acute inflammation in vivo, neutralizing the effect of exogenously administered human IL-1β and blocking peritonitis in a mouse model of acute gout. Based on its high potency, novel mechanism of action, long half-life, and high affinity, XOMA 052 provides a new strategy for the treatment of a number of inflammatory, autoimmune and metabolic diseases in which the role of IL-1β is central to pathogenesis.
Journal of Biological Chemistry | 2010
Marina Roell; Hassan Issafras; Robert J. Bauer; Kristen Michelson; Nerissa Mendoza; Sandra Vanegas; Lisa M. Gross; Paul Larsen; Daniel Bedinger; David J. Bohmann; Genevieve Nonet; Naichi Liu; Steve R. Lee; Masahisa Handa; Seema S. Kantak; Arnold Horwitz; John J. Hunter; Alexander Owyang; Amer M. Mirza; John A. Corbin; Mark L. White
Many therapeutic antibodies act as antagonists to competitively block cellular signaling pathways. We describe here an approach for the therapeutic use of monoclonal antibodies based on context-dependent attenuation to reduce pathologically high activity while allowing homeostatic signaling in biologically important pathways. Such attenuation is achieved by modulating the kinetics of a ligand binding to its various receptors and regulatory proteins rather than by complete blockade of signaling pathways. The anti-interleukin-1β (IL-1β) antibody XOMA 052 is a potent inhibitor of IL-1β activity that reduces the affinity of IL-1β for its signaling receptor and co-receptor but not for its decoy and soluble inhibitory receptors. This mechanism shifts the effective dose response of the cytokine so that the potency of IL-1β bound by XOMA 052 is 20–100-fold lower than that of IL-1β in the absence of antibody in a variety of in vitro cell-based assays. We propose that by decreasing potency of IL-1β while allowing binding to its clearance and inhibitory receptors, XOMA 052 treatment will attenuate IL-1β activity in concert with endogenous regulatory mechanisms. Furthermore, the ability to bind the decoy receptor may reduce the potential for accumulation of antibody·target complexes. Regulatory antibodies like XOMA 052, which selectively modulate signaling pathways, may represent a new mechanistic class of therapeutic antibodies.
Journal of Pharmacology and Experimental Therapeutics | 2013
Hassan Issafras; John A. Corbin; Ira D. Goldfine; Marina Roell
Interleukin-1β (IL-1β) is a proinflammatory cytokine that is implicated in many autoinflammatory disorders, but is also important in defense against pathogens. Thus, there is a need to safely and effectively modulate IL-1β activity to reduce pathology while maintaining function. Gevokizumab is a potent anti–IL-1β antibody being developed as a treatment for diseases in which IL-1β has been associated with pathogenesis. Previous data indicated that gevokizumab negatively modulates IL-1β signaling through an allosteric mechanism. Because IL-1β signaling is a complex, dynamic process involving multiple components, it is important to understand the kinetics of IL-1β signaling and the impact of gevokizumab on this process. In the present study, we measured the impact of gevokizumab on the IL-1β system using Schild analysis and surface plasmon resonance studies, both of which demonstrated that gevokizumab decreases the binding affinity of IL-1β for the IL-1 receptor type I (IL-1RI) signaling receptor, but not the IL-1 counter-regulatory decoy receptor (IL-1 receptor type II). Gevokizumab inhibits both the binding of IL-1β to IL-1RI and the subsequent recruitment of IL-1 accessory protein primarily by reducing the association rates of these interactions. Based on this information and recently published structural data, we propose that gevokizumab decreases the association rate for binding of IL-1β to its receptor by altering the electrostatic surface potential of IL-1β, thus reducing the contribution of electrostatic steering to the rapid association rate. These data indicate, therefore, that gevokizumab is a unique inhibitor of IL-1β signaling that may offer an alternative to current therapies for IL-1β–associated autoinflammatory diseases.
Journal of Pharmacology and Experimental Therapeutics | 2015
Daniel Bedinger; Ira D. Goldfine; John A. Corbin; Marina Roell; Sean H. Adams
The monoclonal antibody XMetA is an allosteric partial agonist of the insulin receptor (IR), which activates the metabolic Akt kinase signaling pathway while having little or no effect on the mitogenic extracellular signal‐regulated kinase (ERK) signaling pathway. To investigate the nature of this selective signaling, we have conducted a detailed investigation of XMetA to evaluate specific phosphorylation and activation of IR, Akt, and ERK in Chinese hamster ovary cell lines expressing either the short or long isoform of the human IR. Insulin activated both pathways, but the phosphorylation of Akt was more sensitive to the hormone than the phosphorylation of ERK. Maximally effective concentrations of XMetA elicited phosphorylation patterns similar to 40–100 pM insulin, which were sufficient for robust Akt phosphorylation, but had little effect on ERK phosphorylation. These data indicate that the preferential signaling of XMetA is due to an innate difference in pathway sensitivity of Akt versus ERK responses to IR activation and partial agonism by XMetA, rather than a separate pathway-biased mechanism. The metabolic selectivity of partial IR agonists like XMetA, if recapitulated in vivo, may be a desirable feature of therapeutic agents designed to regulate blood glucose levels while minimizing undesirable outcomes of excessive IR mitogenic activation.
Journal of Cellular Biochemistry | 2015
Daniel Bedinger; Dorothy A. Kieffer; Ira D. Goldfine; Marina Roell; Sean H. Adams
It has been proposed that monoclonal antibodies may become therapeutics for metabolic diseases such as diabetes mellitus. We have previously characterized an allosteric monoclonal antibody to the human insulin receptor (IR), XMetA, that activated metabolic signaling leading to enhanced glucose transport in cultured cells, and chronically reduced fasting blood glucose levels in mouse models of diabetes mellitus. Under acute dosing conditions, the large size of an IR‐binding antibody like XMetA (∼150 kDa) could lead to a more rapid access into liver, an insulin sensitive tissue with well‐fenestrated capillaries, when compared to other insulin sensitive tissues with non‐fenestrated capillaries, such as muscle and adipose. Thus, in the present study we administered XMetA (10 mg/kg) and insulin (0.5 U/kg) via IV injection, and for 90 min compared their effects on blood glucose lowering and IR activation in three of the major insulin‐sensitive tissues of the normal fasted mouse: liver, adipose, and muscle. Like insulin, XMetA lowered blood glucose levels, although the effect was less rapid. Insulin activated IR autophosphorylation and Akt phosphorylation in liver, fat, and muscle. In contrast, IR activation by XMetA was primarily observed in the liver. Both insulin and XMetA lowered β‐hydroxybutyrate levels in plasma; however, only insulin reduced both non‐esterified fatty acids (NEFA) and glycerol concentrations. These data indicate that, in normal mice, acute glucose regulation by XMetA is largely mediated by its action on the liver. J. Cell. Biochem. 116: 2109–2119, 2015.
Biochemical Pharmacology | 2008
Ssucheng J. Hsu; Amita Patel; Paul Larsen; David J. Bohmann; Robert J. Bauer; Jeremy Ma; Linda Masat; Marina Roell; Susan J. Babuka; Rhonda K. Hansen; Mark P. White; Mary Haak-Frendscho
The peptide hormone gastrin is a key factor in regulation of gastric acid secretion. It has also been implicated in the development or maintenance of various types of cancer, such as pancreatic and stomach carcinoma. Inhibition of gastrin activity has potential for therapeutic use as a suppressor of acid secretion as well as an inhibitor of gastrin-responsive tumors. XPA067.06 is an affinity matured, 30 pM fully human anti-gastrin monoclonal antibody that was generated. The antibody was tested in a mouse gastric pH model to determine its effect on acid secretion. In this model, animals were treated with human gastrin, XPA067.06, and H2R or M1 receptor antagonists. Gastric fluid was collected and acid output was measured as a function of pH. XPA067.06 was shown to significantly inhibit gastrin-17-stimulated acid output for at least 48h. These results demonstrate that XPA067.06 effectively binds and neutralizes human gastrin-17 in vivo with rapid onset and prolonged duration of efficacy.
Analytical Biochemistry | 2006
Phinikoula S. Katsamba; Iva Navratilova; María Calderón-Cacia; Linsey Fan; Kevin Thornton; Mingde Zhu; Tim Vanden Bos; Carla Forte; Della Friend; Ite A. Laird-Offringa; Gisele Tavares; John Whatley; Ergang Shi; Angela Widom; Kevin Lindquist; Scott Klakamp; Andrew W. Drake; David J. Bohmann; Marina Roell; Larry Rose; Jill Dorocke; Bruce Roth; Béatrice Luginbühl; David G. Myszka
Archive | 2007
Gang Chen; Linda Masat; Mary Haak-Frendscho; Arnold Horwitz; Marina Roell
Archive | 2006
Linda Masat; Mary Haak-Frendscho; Gang Chen; Arnold Horwitz; Marina Roell
Archive | 2009
Linda Masat; Mary Haak-Frendscho; Arnold Horwitz; Gang Chen; Marina Roell