Biotechnology Discovery Research

Discovery, Colombia

Biotechnology Discovery Research

Discovery, Colombia
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Datta-Mannan A.,Eli Lilly and Company | Chow C.-K.,Biotechnology Discovery Research | Dickinson C.,Discovery Research | Driver D.,Discovery Research | And 3 more authors.
Drug Metabolism and Disposition | Year: 2012

The pH-dependent binding of IgGs to the neonatal Fc receptor (FcRn) plays a critical role in regulating IgG homeostasis in vivo. Enhancing interactions between Fc and FcRn via protein engineering has been successfully used as an approach for improving the pharmacokinetics of monoclonal antibodies (mAbs). Although the quantitative translatability of the in vitro FcRn affinity enhancement to an in vivo pharmacokinetic benefit has been supported by several studies, there are also published reports indicating a disconnect in this relation. The body of literature suggests there are likely additional biochemical and biophysical properties of the mAbs along with their FcRn affinity that influence the in vivo pharmacokinetics. Herein, we more broadly evaluate the in vitro Fc-FcRn interactions and biochemical properties of five humanized IgG4 antibodies each with two Fc variant sequences (T250Q/M428L and V308P) and their corresponding pharmacokinetics in cynomolgus monkeys. Our findings indicate that the FcRn affinity-pharmacokinetic relationship does not show a direct correlation either across different IgGs or between the two variant sequences within a platform. Other parameters that have been suggested to contribute to mAb pharmacokinetic properties, such as the pH-dependent dissociation of the FcRn-IgG complexes, mAb biophysical properties, and nonspecific/charge binding characteristics of the mAbs, also did not independently explain the differing pharmacokinetic behaviors. Our results suggest that there is likely not a single in vitro parameter that readily predicts in vivo pharmacokinetics, but that the relative contribution and interplay of several factors along with the FcRn binding affinity are important determinants of mAb pharmacokinetic properties. Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics.


Breyer M.D.,Biotechnology Discovery Research
Expert Opinion on Drug Discovery | Year: 2014

The pharmaceutical industry is confronted by increasing costs of clinical development and diminishing productivity. The most challenging aspect of drug development has been the failure of therapeutics in expensive Phase II or III trials, and this is most commonly due to lack of efficacy. More can be done during the drug discovery phase to optimize efficacy-testing in animal models by expending resources to explore the congruence of the animal model with the human disease. Historically, relatively little attention has been paid to validation of these models, but access to molecular mRNA and genetic profiling offers a new lens through which the similarity of these disease models to human diseases can be examined and their utility for exploring therapeutic efficacy can be optimized. Exploring congruent experimental end points in clinical and preclinical experiments will also increase confidence of success in late phase clinical development. The expense of this investment is trivial compared to the costs of a failed clinical trial, more than justifying this endeavor. © 2014 Informa UK, Ltd.


Sonnweber T.,Innsbruck Medical University | Nachbaur D.,Innsbruck Medical University | Schroll A.,Innsbruck Medical University | Nairz M.,Innsbruck Medical University | And 16 more authors.
Gut | Year: 2014

Objective: Hypoxia affects body iron homeostasis; however, the underlying mechanisms are incompletely understood. Design: Using a standardised hypoxia chamber, 23 healthy volunteers were subjected to hypoxic conditions, equivalent to an altitude of 5600 m, for 6 h. Subsequent experiments were performed in C57BL/6 mice, CREB-H knockout mice, primary hepatocytes and HepG2 cells. Results: Exposure of subjects to hypoxia resulted in a significant decrease of serum levels of the master regulator of iron homeostasis hepcidin and elevated concentrations of platelet derived growth factor (PDGF)-BB. Using correlation analysis, we identified PDGF-BB to be associated with hypoxia mediated hepcidin repression in humans. We then exposed mice to hypoxia using a standardised chamber and observed downregulation of hepatic hepcidin mRNA expression that was paralleled by elevated serum PDGF-BB protein concentrations and higher serum iron levels as compared with mice housed under normoxic conditions. PDGF-BB treatment in vitro and in vivo resulted in suppression of both steady state and BMP6 inducible hepcidin expression. Mechanistically, PDGF-BB inhibits hepcidin transcription by downregulating the protein expression of the transcription factors CREB and CREB-H, and pharmacological blockade or genetic ablation of these pathways abrogated the effects of PDGF-BB toward hepcidin expression. Conclusions: Hypoxia decreases hepatic hepcidin expression by a novel regulatory pathway exerted via PDGF-BB, leading to increased availability of circulating iron that can be used for erythropoiesis. © 2014 BMJ Publishing Group Ltd & British Society of Gastroenterology.


Yaden B.,Musculoskeletal Research | Yaden B.,Indiana University – Purdue University Indianapolis | Yaden B.,Eli Lilly and Company | Krishnan V.,Musculoskeletal Research | And 3 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2013

Human follistatin is a regulatory glycoprotein with widespread biologic functions, including antiinflammatory activities, woundhealing properties, and muscle-stimulating effects. The role of follistatin in a wide range of biologic activities shows promise for potential clinical application, which has prompted considerable interest in the investigation of the protein as a potential diseasemodifying agent. In spite of this potential, the development of follistatin as a broad use biotherapeutic has been severely hindered by a poor understanding and characterization of its pharmacokinetic/pharmacodynamic (PK/PD) relationships.Therefore, to better define these relationships, we performed in-depth analyses of the PK/PD relationships of native follistatin-315 (FST315). Our data indicate that the intrinsic PK/PD properties of native FST315 are poorly suited for acting as a parentally administered biotherapeutic with broad systemic effects. Here, we leveraged protein engineering to modify the PK characteristics of the native molecule by fusing FST315 to a murine IgG1 Fc and removing the intrinsic heparan sulfate-binding activity of follistatin. The engineered variant molecule had ̃100- and ̃1600-fold improvements in terminal half-life and exposure, respectively. In contrast to the native FST315, the variant showed a robust, dose-dependent pharmacological effect when administered subcutaneously on a weekly basis in mouse models of muscle atrophy and degeneration. These studies highlight the underappreciated and critical relationship between optimizing multiple physical and chemical properties of follistatin on its overall PK/PD profile. Moreover, our findings provide the first documented strategy toward the development of a follistatin therapeutic with potential use in patients affected with skeletal muscle diseases. © 2013 by The American Society for Pharmacology and Experimental Therapeutics.


Smith R.C.,Biotechnology Discovery Research | Smith R.C.,Lilly Corporate Center | Lin B.K.,Eli Lilly and Company
Current Opinion in Supportive and Palliative Care | Year: 2013

Purpose of review: This review summarizes recent progress in the development of myostatin inhibitors for the treatment of muscle wasting disorders. It also focuses on findings in myostatin biology that may have implications for the development of antimyostatin therapies. Recent findings: There has been progress in evaluating antimyostatin therapies in animal models of muscle wasting disorders. Some programs have progressed into clinical development with initial results showing positive impact on muscle volume. In normal mice myostatin deficiency results in enlarged muscles with increased total force but decreased specific force (total force/total mass). An increase in myofibrillar protein synthesis without concomitant satellite cell proliferation and fusion leads to muscle hypertrophy with unchanged myonuclear number. A specific force reduction is not observed when atrophied muscle, the predominant therapeutic target of myostatin inhibitor therapy, is made myostatindeficient. Myostatin has been shown to be expressed by a number of tumor cell lines in mice and man. Summary: Myostatin inhibition remains a promising therapeutic strategy for a range of muscle wasting disorders. Copyright © 2013 Wolters Kluwer Health.


Breyer M.D.,Biotechnology Discovery Research | Qi Z.,Biotechnology Discovery Research
Kidney International | Year: 2010

The use of creatinine to estimate glomerular filtration rate in patients is prone to well-described artifacts that impact its interpretation. Eisner et al. now show that the impact of creatinine secretion on creatinine clearance is even larger in mice than in humans, raising questions regarding the utility of creatinine for measuring glomerular filtration rate in mice. © 2010 International Society of Nephrology.


Tanaka K.,Kyoto University | Tanaka K.,Japan Science and Technology Agency | Furuyashiki T.,Kyoto University | Furuyashiki T.,Japan Science and Technology Agency | And 9 more authors.
Journal of Neuroscience | Year: 2012

Various kinds of stress are thought to precipitate psychiatric disorders, such as major depression. Whereas studies in rodents have suggested a critical role of medial prefrontal cortex (mPFC) in stress susceptibility, the mechanism of how stress susceptibility is determined through mPFC remains unknown. Here we show a critical role of prostaglandin E 2 (PGE 2), a bioactive lipid derived from arachidonic acid, in repeated social defeat stress in mice. Repeated social defeat increased the PGE 2 level in the subcortical region of the brain, and mice lackingeither COX-1,aprostaglandin synthase,orEP1,aPGE receptor, were impairedininductionofsocial avoidanceby repeated social defeat. Given the reported action of EP1 that augments GABAergic inputs to midbrain dopamine neurons, we analyzed dopaminergic response upon social defeat. Analyses of c-Fos expression of VTA dopamine neurons and dopamine turnover in mPFC showed that mesocortical dopaminergic pathway is activated upon social defeat and attenuated with repetition of social defeat in wild-type mice. EP1 deficiency abolished such repeated stress-induced attenuation of mesocortical dopaminergic pathway. Blockade of dopamine D1-like receptor during social defeat restored social avoidance in EP1-deficient mice, suggesting that disinhibited dopami-nergic response during social defeat blocks induction of social avoidance. Furthermore, mPFC dopaminergic lesion by local injection of 6-hydroxydopamine, which mimicked the action of EP1 during repeated stress, facilitated induction of social avoidance upon social defeat. Taken together, our data suggest that PGE 2-EP1 signaling is critical for susceptibility to repeated social defeat stress in mice through attenuation of mesocortical dopaminergic pathway. © 2012 the authors.


Breyer M.D.,Biotechnology Discovery Research
Seminars in Nephrology | Year: 2012

Diabetic nephropathy is the single major cause of kidney failure in the industrialized world and given the emerging global pandemic of diabetes mellitus, its prevalence is expected to only increase. Because of the lack of dynamic biomarkers that define the rate of kidney function loss, there are few proof-of-concept clinical trials for new therapeutics to treat diabetic nephropathy. A molecular understanding of the pathogenesis of diabetic nephropathy also is lacking. These deficiencies are magnified by the fact that most mouse models of diabetic nephropathy fail to show progressive kidney disease. Recently, some mouse models that showed requisite phenotypic changes of diabetic nephropathy have been identified. Validation of results obtained in these experimental models, and showing whether they accurately can predict clinical response to therapeutics in human diabetic nephropathy, must now be established.© 2012 Elsevier Inc.


Schouten M.,University of Amsterdam | van't Veer C.,University of Amsterdam | Roelofs J.J.T.H.,University of Amsterdam | Gerlitz B.,Biotechnology Discovery Research | And 3 more authors.
Thrombosis and Haemostasis | Year: 2011

Recombinant human activated protein C (APC), which has both anticoagulant and anti-inflammatory properties, improves survival of patients with severe sepsis. This beneficial effect is especially apparent in patients with pneumococcal pneumonia. Earlier treatment with APC in sepsis has been associated with a better therapeutic response as compared to later treatment. In a mouse model it was recently confirmed that recombinant murine (rm-)APC decreases coagulation activation and improves survival in pneumococcal pneumonia; however, APC did not impact on the inflammatory response. The aim of this study was to determine the effect of APC treatment instigated early in infection on activation of coagulation and inflammation after induction of pneumococcal pneumonia. Mice were infected intranasally with viable S. pneumoniae. Mice were treated with rm-APC (125μg) or vehicle intraperi- toneally 12 hours after infection and were sacrificed after 20 hours, after which blood and organs were harvested for determination of bacterial outgrowth, coagulation activation and inflammatory markers. In this early treatment model, rm-APC treatment inhibited pulmonary and systemic activation of coagulation as reflected by lower levels of thrombin- antithrombin complexes and D-dimer. Moreover, rm-APC reduced the levels of a large number of cytokines and chemokines in the lung. When administered early in pneumococcal pneumonia, rm-APC inhibits systemic and pulmonary activation of coagulation and moreover exerts various anti-inflammatory effects in the lung. © Schattauer 2011.


Breyer M.D.,Biotechnology Discovery Research
Contributions to Nephrology | Year: 2011

The laboratory mouse is among the best characterized and flexible experimental platforms available for the study of diabetic nephropathy (DN). However, studies of progressive kidney disease in mice have underscored several important technical considerations for accurate phenotyping of renal function. Most mouse models of DN fail to exhibit progressive kidney disease. However, a few models have proved particularly useful. Despite the utility of these models, whether they can accurately predict clinical benefit of therapeutics in human DN remains to be established. Copyright © 2011 S. Karger AG, Basel.

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