Glyco-engineered Long Acting FGF21 Variant with Optimal Pharmaceutical and Pharmacokinetic Properties to Enable Weekly to Twice Monthly Subcutaneous Dosing

[1]  Lei Zhou,et al.  A Novel Fc-FGF21 With Improved Resistance to Proteolysis, Increased Affinity Toward &bgr;-Klotho, and Enhanced Efficacy in Mice and Cynomolgus Monkeys , 2017, Endocrinology.

[2]  Jeffrey R. Chabot,et al.  A Long-Acting FGF21 Molecule, PF-05231023, Decreases Body Weight and Improves Lipid Profile in Non-human Primates and Type 2 Diabetic Subjects. , 2016, Cell metabolism.

[3]  E. Liu,et al.  First-In-Human safety and long-term exposure data for AAB-003 (PF-05236812) and biomarkers after intravenous infusions of escalating doses in patients with mild to moderate Alzheimer’s disease , 2016, Alzheimer's Research & Therapy.

[4]  R. DiMarchi,et al.  FGF21 Revolutions: Recent Advances Illuminating FGF21 Biology and Medicinal Properties , 2015, Trends in Endocrinology & Metabolism.

[5]  Yali Liang,et al.  Pharmacokinetics and pharmacodynamics of PF-05231023, a novel long-acting FGF21 mimetic, in a first-in-human study. , 2015, British journal of clinical pharmacology.

[6]  T. Rolph,et al.  FGF21 does not require interscapular brown adipose tissue and improves liver metabolic profile in animal models of obesity and insulin-resistance , 2015, Scientific Reports.

[7]  Denise M O'Hara,et al.  Faster in vivo clearance of human embryonic kidney than Chinese hamster ovary cell derived protein: Role of glycan mediated clearance. , 2015, Journal of bioscience and bioengineering.

[8]  Y. Weng,et al.  Mechanistic Investigation of the Preclinical Pharmacokinetics and Interspecies Scaling of PF-05231023, a Fibroblast Growth Factor 21–Antibody Protein Conjugate , 2015, Drug Metabolism and Disposition.

[9]  Matthew J. Brauer,et al.  Sustained Brown Fat Stimulation and Insulin Sensitization by a Humanized Bispecific Antibody Agonist for Fibroblast Growth Factor Receptor 1/βKlotho Complex , 2015, EBioMedicine.

[10]  Jeffrey R. Chabot,et al.  Pharmacokinetics (PK), Pharmacodynamics (PD) and Integrated PK/PD Modeling of a Novel Long Acting FGF21 Clinical Candidate PF-05231023 in Diet-Induced Obese and Leptin-Deficient Obese Mice , 2015, PloS one.

[11]  Li Li,et al.  Rational design of viscosity reducing mutants of a monoclonal antibody: Hydrophobic versus electrostatic inter-molecular interactions , 2015, mAbs.

[12]  Daniel Lindén,et al.  Monoclonal Antibody Targeting of Fibroblast Growth Factor Receptor 1c Ameliorates Obesity and Glucose Intolerance via Central Mechanisms , 2014, PloS one.

[13]  Dongmei Li,et al.  Fibroblast Growth Factor 21 Improves Insulin Sensitivity and Synergizes with Insulin in Human Adipose Stem Cell-Derived (hASC) Adipocytes , 2014, PloS one.

[14]  D. Moller,et al.  FGF21-based pharmacotherapy – potential utility for metabolic disorders , 2014, Trends in Endocrinology & Metabolism.

[15]  Yang Li,et al.  Fibroblast growth factor 21, the endocrine FGF pathway and novel treatments for metabolic syndrome. , 2014, Drug discovery today.

[16]  A. Adams,et al.  Inventing new medicines: The FGF21 story☆ , 2013, Molecular metabolism.

[17]  H. Fu,et al.  The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. , 2013, Cell metabolism.

[18]  K. Retting,et al.  Development of a Novel Long-Acting Antidiabetic FGF21 Mimetic by Targeted Conjugation to a Scaffold Antibody , 2013, The Journal of Pharmacology and Experimental Therapeutics.

[19]  B. Hansen,et al.  LY2405319, an Engineered FGF21 Variant, Improves the Metabolic Status of Diabetic Monkeys , 2013, PloS one.

[20]  Christopher C. Frye,et al.  Rational Design of a Fibroblast Growth Factor 21-Based Clinical Candidate, LY2405319 , 2013, PloS one.

[21]  Todd Hager,et al.  Differential enzyme-linked immunosorbent assay and ligand-binding mass spectrometry for analysis of biotransformation of protein therapeutics: application to various FGF21 modalities. , 2013, Analytical chemistry.

[22]  Thomayant Prueksaritanont,et al.  The impact of sialic acids on the pharmacokinetics of a PEGylated erythropoietin. , 2012, Journal of pharmaceutical sciences.

[23]  T. Arora,et al.  Treating Diabetes and Obesity with an FGF21-Mimetic Antibody Activating the βKlotho/FGFR1c Receptor Complex , 2012, Science Translational Medicine.

[24]  T. Boone,et al.  Rationale-Based Engineering of a Potent Long-Acting FGF21 Analog for the Treatment of Type 2 Diabetes , 2012, PloS one.

[25]  B. Antonsson,et al.  Differences in the glycosylation of recombinant proteins expressed in HEK and CHO cells. , 2012, Journal of biotechnology.

[26]  S. Kliewer,et al.  βKlotho is required for fibroblast growth factor 21 effects on growth and metabolism. , 2012, Cell metabolism.

[27]  Katherine A. Winters,et al.  Long-acting FGF21 has enhanced efficacy in diet-induced obese mice and in obese rhesus monkeys. , 2012, Endocrinology.

[28]  T. Singer,et al.  Minipig as a potential translatable model for monoclonal antibody pharmacokinetics after intravenous and subcutaneous administration , 2012, mAbs.

[29]  Margaret S. Wu,et al.  FGF21 Analogs of Sustained Action Enabled by Orthogonal Biosynthesis Demonstrate Enhanced Antidiabetic Pharmacology in Rodents , 2012, Diabetes.

[30]  W WarneNicholas,et al.  Development of high concentration protein biopharmaceuticals: the use of platform approaches in formulation development. , 2011 .

[31]  Saileta Prabhu,et al.  Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data , 2011, mAbs.

[32]  B. Meibohm,et al.  Population Pharmacokinetics of Therapeutic Monoclonal Antibodies , 2010, Clinical pharmacokinetics.

[33]  T. Prueksaritanont,et al.  Prediction of human clearance of therapeutic proteins: simple allometric scaling method revisited , 2010, Biopharmaceutics & drug disposition.

[34]  F. Gao,et al.  Transient expression of an IL-23R extracellular domain Fc fusion protein in CHO vs. HEK cells results in improved plasma exposure. , 2010, Protein expression and purification.

[35]  D. Driver,et al.  Different roles of N‐ and C‐ termini in the functional activity of FGF21 , 2009, Journal of cellular physiology.

[36]  M. Mohammadi,et al.  The FGF family: biology, pathophysiology and therapy , 2009, Nature Reviews Drug Discovery.

[37]  J. Xu,et al.  FGF21 N‐ and C‐termini play different roles in receptor interaction and activation , 2009, FEBS letters.

[38]  Jason K. Kim,et al.  Fibroblast Growth Factor 21 Reverses Hepatic Steatosis, Increases Energy Expenditure, and Improves Insulin Sensitivity in Diet-Induced Obese Mice , 2009, Diabetes.

[39]  D. Moller,et al.  Fibroblast growth factor 21 corrects obesity in mice. , 2008, Endocrinology.

[40]  J. D. Dunbar,et al.  FGF‐21/FGF‐21 receptor interaction and activation is determined by βKlotho , 2008, Journal of cellular physiology.

[41]  S. Kliewer,et al.  Tissue-specific Expression of βKlotho and Fibroblast Growth Factor (FGF) Receptor Isoforms Determines Metabolic Activity of FGF19 and FGF21* , 2007, Journal of Biological Chemistry.

[42]  S. Kliewer,et al.  Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. , 2007, Cell metabolism.

[43]  S. Demarest,et al.  A broad range of Fab stabilities within a host of therapeutic IgGs. , 2007, Biochemical and biophysical research communications.

[44]  Yun-Fei Chen,et al.  The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. , 2007, Endocrinology.

[45]  S. Elliott,et al.  Glycoengineering: the effect of glycosylation on the properties of therapeutic proteins. , 2005, Journal of pharmaceutical sciences.

[46]  J. Gromada,et al.  FGF-21 as a novel metabolic regulator. , 2005, The Journal of clinical investigation.

[47]  J. Egrie,et al.  Darbepoetin alfa has a longer circulating half-life and greater in vivo potency than recombinant human erythropoietin. , 2003, Experimental hematology.

[48]  L. Buck,et al.  Enhancement of therapeutic protein in vivo activities through glycoengineering , 2003, Nature Biotechnology.

[49]  M. Nussenzweig,et al.  Mannose Receptor-Mediated Regulation of Serum Glycoprotein Homeostasis , 2002, Science.

[50]  J. Egrie,et al.  Development and characterization of novel erythropoiesis stimulating protein (NESP) , 2001, British Journal of Cancer.

[51]  B. Imperiali,et al.  Effect of N-linked glycosylation on glycopeptide and glycoprotein structure. , 1999, Current opinion in chemical biology.

[52]  G. Winter,et al.  The binding site for C1q on IgG , 1988, Nature.

[53]  D. Burton,et al.  Localization of the binding site for the human high-affinity Fc receptor on IgG , 1988, Nature.

[54]  E Bause,et al.  The role of the hydroxy amino acid in the triplet sequence Asn-Xaa-Thr(Ser) for the N-glycosylation step during glycoprotein biosynthesis. , 1981, The Biochemical journal.

[55]  N. Warne,et al.  Development of high concentration protein biopharmaceuticals: the use of platform approaches in formulation development. , 2011, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[56]  A. Morell,et al.  The dual role of sialic acid in the hepatic recognition and catabolism of serum glycoproteins. , 1974, Biochemical Society symposium.