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Peginterferon Lambda-1a, a New Therapeutic for Hepatitis C Infection, from Bench to Clinic

Journal of Clinical and Translational Hepatology 2013年第2期1卷 116-124页

作者： Henrik Andersen Jeff Meyer Jeremy Freeman Sean E.Doyle Kevin Klucher Dennis M.Miller Diana Hausman Jan L.Hillson ZymoGenetics/Bristol-Myers Squibb Seattle WA 98102 USA emd serono Billerica MA USA Oncothyreon Inc. Seattle WA USA CPTxBio Woodinville WA USA

Chronic infection with hepatitis C virus (HCV) is estimated to affect approximately 3% of the world's population and cause 350,000 deaths each *** number of years,the standard of care has been combination therapy with recombinant alfa interferons—originally as native proteins but more recently as polyethyleneglycol-modified derivatives—and ribavirin,with the recent addition of an NS3 protease inhibitor for HCV genotype ***,therapeutic alfa interferons are associated with a significant burden of treatment-limiting adverse events,including musculoskeletal and influenza-like symptoms,hematologic cytopenias,autoimmune disease,fatigue,and other neurologic *** 2003,a team at ZymoGenetics (now a fully owned subsidiary of Bristol-Myers Squibb) and a second,independent group simultaneously identified a new class of interferons—the type Ⅲ lambda interferons—with near-identical activity to the type Ⅰ alfa interferons in hepatocytes but with an unrelated and less ubiquitous *** evaluation of the type Ⅲ interferon system demonstrated antiviral activity against HCV in vitro with limited activity in peripheral blood mononuclear cells and other nonhepatocyte cell types,supporting its development as a potentially better-tolerated therapy for viral *** lambda-1a (Lambda) is an investigational type Ⅲ therapeutic agent originally developed at ZymoGenetics that is currently in Phase 3 studies for the treatment of *** this review,we describe the selection of the Lambda molecule and its preclinical and early clinical development,and how the resulting data have helped to establish the differentiated safety profile for Lambda—with fewer influenza-like and musculoskeletal symptoms and less hematologic toxicity than the alfa interferons—that was seen in later studies.

关键词： Discovery HCV Interferonλ

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Using high-throughput data and dynamic flux balance modeling techniques to identify points of constraint in xylose utilization in Saccharomyces cerevisiae

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Systems Microbiology and Biomanufacturing 2021年第1期1卷 58-75页

作者： William Hohenschuh Ronald E.Hector Frank Chaplen Ganti S.Murthy Oregon State University CorvallisUSA USDA ARSNCAURPeoriaUSA Present Address:emd serono Inc. RocklandUSA Present Address:Indian Institute of Technology-Indore IndoreIndia

Background Several enzymes and cofactors have been identified as contributing to the slow utilization of xylose by xylose-fermenting strains of Saccharomyces ***,there has been no consensus on which of these possible bottle-necks are the most important to address.A previous strain characterization study from our lab suggested that insufficient NAD+limits fermentation and may be the most important bottleneck affecting utilization of xylose for the production of *** development and validation of a genome scale dynamic flux balance model would help to verify the existence and extent of this and other metabolic bottlenecks and suggest solutions to guide future strain development thereby minimiz-ing bottleneck impact on process *** A dynamic flux balance model was developed to identify bottlenecks in several strains of ***,both with wild-type pentose phosphate pathway expression and with the pathway over ***1 was found to be limiting in the oxidative portion of the pentose phosphate pathway under oxygen replete *** pathway is used to regenerate *** oxygen limiting conditions,respiration of xylose was limited by the lack of oxygen as a terminal electron *** production was also limited under these conditions due to the inability to balance NAD+/*** model suggests the use of the anaplerotic glyoxylate pathway to improve NAD+/NADH balance,increasing ethanol produc-tion by 50%while producing succinate as a coproduct at upwards of 20 g/*** In the production of high value chemicals from biomass,the use of the respiratory metabolism is a waste of feedstock *** previously identified in the oxidative pentose phosphate pathway are currently only relevant under oxygen-replete conditions and cannot impact the partitioning of carbon between the respiratory and fermentative *** future efforts on the non-respiratory balancing of NAD+/NADH,perhaps through th

关键词： Xylose Ethanol Biofuel Lignocellulose Metabolic bottlenecks Flux balance analysis Modeling Cofactor imbalance Glyoxylate pathway NAD+ NADH

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Mathematical Analysis of the Meridian System in Traditional Chinese Medicine

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Digital Chinese Medicine 2020年第3期3卷 141-147页

作者： WAN Xiao-Hai emd serono Research&Development Institute BillericaMassachusetts 01821-3936USA

Energy expenditure of the meridian system in traditional Chinese medicine(TCM)for living human bodies is one of the fundamental questions regarding the physical properties of the meridian *** a first attempt to address this,24 hand/foot meridians were modeled as a continuous channel with the sustainable movement of Qi and blood ***,the fluid mechanics energy equation for steady and incompressible flow was applied to estimate the pumping power of meridian circulation,based on the meridian length,blood viscosity and circulation *** findings based on the pumping power estimation results include:(1)new information to corroborate the determination of the production era of Yellow Emperor’s Inner Classics(Huang Di Nei Jing,《黄帝内经》);(2)a new definition for work of breathing(WOB)from a TCM *** paper could lead to future research aimed at modernizing the understanding of the meridian system,Qi and TCM using quantitative methods.

关键词： Meridian system Pumping power Fluid mechanics Human physiology Work of breathing

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Implications of metabolism-driven myeloid dysfunctions in cancer therapy

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Cellular & Molecular Immunology 2021年第4期18卷 829-841页

作者： Laura Strauss Valentina Guarneri Alessandra Gennari Antonio Sica Department of Immunopharmacology and Immuno Oncology EMD Serono Research&Development InstituteInc.80119545A Middlesex TurnpikeBillericaMA 01821USA Department of Surgery Oncology and GastroenterologyUniversity of PadovaPadovaItaly Veneto Institute of Oncology-IRCCS PaduaItalyPadovaItaly Division of Oncology Department of Translational MedicineUniversity of Eastern PiedmontNovaraItaly Department of Pharmaceutical Sciences University of Eastern PiedmontA.Avogadrovia Bovio 6NovaraItaly Humanitas Clinical and Research Center IRCCSVia Manzoni 56RozzanoMilanItaly

Immune homeostasis is maintained by an adequate balance of myeloid and lymphoid *** chronic inflammatory states,including cancer,this balance is lost due to dramatic expansion of myeloid progenitors that fail to mature to functional inflammatory neutrophils,macrophages,and dendritic cells(DCs),thus giving rise to a decline in the antitumor effector lymphoid ***-related inflammation orchestrates the production of hematopoietic growth factors and cytokines that perpetuate recruitment and activation of myeloid precursors,resulting in unresolved and chronic *** pathologic inflammation creates profound alterations in the intrinsic cellular metabolism of the myeloid progenitor pool,which is amplified by competition for essential nutrients and by hypoxia-induced metabolic rewiring at the tumor ***,persistent myelopoiesis and metabolic dysfunctions contribute to the development of cancer,as well as to the severity of a broad range of diseases,including metabolic syndrome and autoimmune and infectious *** aims of this review are to(1)define the metabolic networks implicated in aberrant myelopoiesis observed in cancer patients,(2)discuss the mechanisms underlying these clinical manifestations and the impact of metabolic perturbations on clinical outcomes,and(3)explore new biomarkers and therapeutic strategies to restore immunometabolism and differentiation of myeloid cells towards an effector phenotype to increase host antitumor *** propose that the profound metabolic alterations and associated transcriptional changes triggered by chronic and overactivated immune responses in myeloid cells represent critical factors influencing the balance between therapeutic efficacy and immune-related adverse effects(irAEs)for current therapeutic strategies,including immune checkpoint inhibitor(ICI)therapy.

关键词： Myelopoiesis Tumor-associated macrophages Myeloid-derived suppressor cells Metabolism Cancer therapy

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Development and characterization of Saccharomyces cerevisiae strains genetically modified to over-express the pentose phosphate pathway regulating transcription factor STB5 in the presence of xylose

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Systems Microbiology and Biomanufacturing 2021年第1期1卷 42-57页

作者： William Hohenschuh Ronald E.Hector Jeffrey A.Mertens Ganti S.Murthy Biological and Ecological Engineering Oregon State University116 Gilmore HallCorvallisOR 97331USA USDA ARSNCAURPeoriaIL 61604USA Present Address:emd serono Inc. RocklandMA 02370USA Present Address:Biosciences and Biomedical Engineering Indian Institute of Technology-IndorePOD 1A704 Khandwa RoadSimrolMadhya Pradesh 453552India

Background Several enzymes in the pentose phosphate pathway of Saccharomyces cerevisiae have been identified as relating to the constraint of xylose consumption and conversion to ***,no strategy has been proposed for simultaneous regulation of all contributing *** multiple enzymes contribute to constraint,over expression of a native transcription factor controlling the entire constraining pathway may provide optimal pathway wide *** characterization of this strain on both pure sugars and lignocellulosic hydrolysates would provide an opportunity to identify additional bot-tlenecks not addressed by the modification of the pentose phosphate pathway expression *** A series of strains were developed expressing STB5 and PGI1 under the control of a novel xylose inducible *** transcription of STB5 and its regulatory targets was verified via *** statistically significant difference was found in terms of xylose consumption or ethanol yield in these strains versus control *** consumption through both the fermentative and respiratory pathways appeared to be related to oxygen availability and culture density with high-density(low oxygen)cultures consuming xylose more slowly than low-density *** maximum specific consumption rate for high-density cultures was 0.21 g xylose/gDCW/h versus 0.41 g xylose/gDCW/h in lower density *** similar ethanol yields at high and low density(approximately 0.25 g ethanol/g xylose)suggest that the maximum rate of fermentation is linked to the rate of respiration in a stoichiometric *** This study did not find evidence supporting the pentose phosphate pathway constraint identified in other ***,NAD+availability mediated by oxygen availability and citric acid cycle flux was suggested to limit *** increased aeration could provide increased conversion of NAD+to NADH(and a stoichiometric increase in fermen-tatio

关键词： Xylose Ethanol Biofuel Lignocellulose Metabolic bottlenecks STB5 Xylose inducible NAD+/NADH Cofactor imbalance Saccharomyces cerevisiae

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Sin1/mTORC2 regulate B cell growth and metabolism by activating mTORC1 and Myc

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Cellular & Molecular Immunology 2019年第9期16卷 757-769页

作者： Man Li Adam S.Lazorchak Xinxing Ouyang Huihui Zhang Hongzhi Liu Omotooke A.Arojo Lichong Yan Jingsi Jin Yuheng Han Guojun Qu Yuhong Fu Xiaocao Xu Xiaobo Liu Wenqian Zhang Zhengfeng Yang Chuan Ruan Qijun Wang Dou Liu Chuanxin Huang Lu Lu Shibo Jiang Fubin Li Bing Su Shanghai Institute of Immunology Department of Immunology and MicrobiologyKey Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of EducationShanghai Jiao Tong University School of MedicineShanghai 200025China Department of Immunobiology and the Vascular Biology and Therapeutics Program Yale University School of Medicine333 Cedar StreetNew HavenConnecticut 06520USA Present address:emd serono Research&Development Institute Inc.45 Middlesex TpkeBillericaMA 01821–3936USA Hongqiao International Institute of Medicine Shanghai Tongren Hospital and Faculty of Basic MedicineShanghai Jiao Tong University School of MedicineShanghai 200025China Shanghai Public Health Clinical Center and School of Basic Medical Sciences Key Laboratory of Medical Molecular Virology of MOE/MOHFudan UniversityShanghaiChina

Proper control of B cell growth and metabolism is crucial for B-cell-mediated immunity,but the underlying molecular mechanisms remain incompletely *** this study,Sin1,a key component of mTOR complex 2(mTORC2),specifically regulates B cell growth and *** ablation of Sin1 in B cells reduces the cell size at either the transitional stage or upon antigen stimulation and severely impairs ***1 deficiency also severely impairs B-cell proliferation,antibody responses,and anti-viral *** the molecular level,Sin1 controls the expression and stability of the c-Myc protein and maintains the activity of mTORC1 through the Akt-dependent inactivation of GSK3 and TSC1/2,***,our study reveals a novel and specific role for Sin1 in coordinating the activation of mTORC2 and mTORC1 to control B cell growth and metabolism.

关键词： metabolism immunity stimulation

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Recent advances in the translation of drug metabolism and pharmacokinetics science for drug discovery and development

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Acta Pharmaceutica Sinica B 2022年第6期12卷 2751-2777页

作者： Yurong Lai Xiaoyan Chu Li Di Wei Gao Yingying Guo Xingrong Liu Chuang Lu Jialin Mao Hong Shen Huaping Tang Cindy Q.Xia Lei Zhang Xinxin Ding Drug Metabolism Gilead Sciences Inc.Foster CityCA 94404USA Department of Pharmacokinetics Pharmacodynamics and Drug MetabolismMerck&Co.Inc.KenilworthNJ 07033USA Pharmacokinetics Dynamics and MetabolismPﬁzer Worldwide Research and DevelopmentGrotonCT 06340USA Eli Lilly and Company IndianapolisIN 46221USA Drug Metabolism and Pharmacokinetics BiogenCambridgeMA 02142USA Drug Metabolism and Pharmacokinetics Accent TherapeuticsInc.LexingtonMA 02421USA Department of Drug Metabolism and Pharmacokinetics GenentechA Member of the Roche GroupSouth San FranciscoCA 94080USA Drug Metabolism and Pharmacokinetics Department Bristol-Myers Squibb CompanyPrincetonNJ 08540USA Bioanalysis and Biomarkers Glaxo Smith KlineKing of the PrussiaPA 19406USA Department of Drug Metabolism and Pharmacokinetics Takeda Pharmaceuticals International Co.CambridgeMA 02139USA Ofﬁce of Research and Standards Ofﬁce of Generic DrugsCDERFDASilver SpringMD 20993USA Department of Pharmacology and Toxicology College of PharmacyUniversity of ArizonaTucsonAZ 85721USA Current afﬁliation:Translational Medicine EMD Serono Research&Development InstituteInc.BillericaMA 01821USA Current afﬁliation:Drug Metabolism Gilead Sciences Inc.Foster CityCA 94404USA

Drug metabolism and pharmacokinetics(DMPK) is an important branch of pharmaceutical *** nature of ADME(absorption,distribution,metabolism,excretion) and PK(pharmacokinetics) inquiries during drug discovery and development has evolved in recent years from being largely descriptive to seeking a more quantitative and mechanistic understanding of the fate of drug candidates in biological *** progress has been made in the past decade,not only in the characterization of physiochemical properties of drugs that influence their ADME,target organ exposure,and toxicity,but also in the identification of design principles that can minimize drug-drug interaction(DDI) potentials and reduce the *** importance of membrane transporters in drug disposition,efficacy,and safety,as well as the interplay with metabolic processes,has been increasingly *** increases in investments on new modalities beyond traditional small and large molecule drugs,such as peptides,oligonucleotides,and antibody-drug conjugates,necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME *** this review,we highlight some of the most notable advances in the last decade,and provide future perspectives on potential major breakthroughs and innovations in the translation of DMPK science in various stages of drug discovery and development.

关键词： Drug discovery and development New drug application Biologics license application Pharmacokinetics ADME New modalities Model-informed drug development Micro-physiological systems

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