Biopharmaceuticals and Glycosylation
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1 Biopharmaceuticals and Glycosylation ABIC, Cork, Ireland August Lokesh Joshi Stokes Professor of Glycosciences Associate Director, Center for BioAnalytical Sciences National University of Ireland Galway In Partnership with:
2 The Market For Glycoprotein Drugs Estimated Annual World Wide Sales of Selected Recombinant Proteins Total Biopharmaceutical Sales (proteins, mabs and nucleic acids) 2004 US $ ~ 33 billion 2010 est US $ ~70 billion Walsh, Nat. Biotech., 2006, 24: Expected Contributions Non-Ab Proteins US $ > 30 billion Pavlou and Reichert, Nat. Biotech., 2004 mabs US $ ~ 20 billion Hiatt and Pauly, PNAS, 2006 Figure: Pavlou and Reichert, Nature Biotechnology 22, (2004)
3 Why do drugs fail? Toxicity and immunogenicity (49%) long term safety is still totally unpredictable Bioavailability and half life (15%) half life cannot be predicted, only guessed Metabolism (3%) drug/drug interactions; parent or metabolite Human Error (33%) Faulty understanding of pathophysiology
4 Structure and Function (Catalytic activity, stability, association, half-life, localization etc.)
5 Representative Post-Translational Modifications PHOSPHORYLATION, AMIDATION, SULFATION, ACETYLATION, CARBOXYMETHYLATION, ADP- RIBOSYLATION, N-TERMINAL CLEAVAGE, C-TERMINAL CLEAVAGE, ASPARAGINE LINKED GLYCOSYALTION, SERINE/THREONINE LINKED GLYCOSYLATION, HYDROXYLYSINE GLYCOSYLATION, HYDROXYPROLINE GLYCOSYLATION, UBIQUITINATION, PROTEOLYTIC CLEAVAGE, CROSS LINKING, NON-ENZYMATIC GLYCATION, HALOGENATION, ADENYLATION, ASPARTYL ISOMERIZATION, DISULFIDE BOND FORMATION, PRENYLATION, METHYLATION, LIPOYLATION, ARGINYLATION, PROLINE HYDROXYLATION, LYSINE HYDROXYLATION, ISOMERIZATION, MYRISTOYLATION, ACYLATION, PALMITOYLATIN, FARNESYLATION, GERANYLGERANYLATION, DEPHOSPHORYLATION, DEAMINATION, DEIMINATION, DEGLYCOSYLATION, DEACYLATION, DESULFATION, DEUBIQUITINATION, ISOPRENYLATION, GPI-ANCHOR, PROTEOGLYCANS
6 Glycosylation The Most Challenging Aspect of Pharmaprotein Engineering -Where the Variation Lies Glycoconjugate complexity E. coli Fungi Plants Insects Fish Mammals Humans
7 N-Glycosylation Pathway Glycoforms Helenius & Aebi. Science, 291, 2001
8 O-Glycosylation Biosynthesis
9 Overview of Sugar Metabolism in Cells Gal ATP Gal-1-P UTP UDP-Glc UDP-Gal NAD Pi Glycogen UDP-Glc NAD+ UDP-GlcA -CO 2 UDP-Xyl GalNAc ATP GalNAc-1-P UTP Dol-P Glc ATP Glc-6-P Glc-1-P Dol-P-Glc UDP-GalNAc GlcNAc ATP Glycolysis -NH 3 GlcNAc-6-P GlcNAc-l-P UDP- GlcNAc ManNAc ATP Fru-6-P Glutamine GlcN-6-P AcCoA UTP Dol-P Man Man-6-P Man-l-P GTP GDP-Man NADP GDP-Fuc Dol-P-Man Fuc ATP Fuc-1- GTP - Synthesis - Activation - Transport - Transfer - Removal CMP-Neu5Ac NADP CMP-Neu5Ac CTP Neu5Ac ManNAc-6-P PEP Neu5Ac-9-P
10 * Asialoglycoprotein Receptors * Hepatic Gal/GalNAc Receptors * Mannose Receptors
11 Factors that can Influence Glycosylation of Biopharma Drugs Protein of Interest Host & expressions system Extracellular ph & buffer system NH 4 accumulation CO 2 accumulation Temperature Nutrient feeds Operating mode (batch vs. perfusion) Harvest times Agitator shear Bioreactor type Manufacturing site
12 Recombinant Protein Glycosylation Sources of heterogeneity Site-occupancy Antennarity Sialylation / Fucosylation Pharmaceutical Relevence Bioactivity Pharmacokinetics Immunogenicity Stability Asn Sialic acid Galactose N-acetylglucosamine Mannose Fucose
13 Serum Half-Life & Clearance The increase of in vivo potency of glycosylated and hyperglycosylated proteins appears to be due to an increase in serum half-life or circulating residence time. Darbepoetin alfa (DA) (hyperglycosylated rhepo) exhibits approx 3-fold longer half-life in humans. FSH isoforms with high sialic acid content were found to have reduced renal clearance and increased in vivo bioactivity. Hyperglycosylated FSH had 3-4 fold increased half-life, enhancing its in vivo bioactivity.
14 Serum Half-Life & Clearance repo serum half-life Non-silaylated 2 min Sialylated - 3 hr rfactor VIII serum half-life Non-silaylated 5 min Sialylated - 4 hr Ngantung et al., 2006
15 Most Biopharmaproteins Induce Antibodies Current analytical methods cannot fully predict biological properties. The immune system can detect alterations in products missed by analytical methdos. Immunogenicity to the biopharmaceuticals may have serious clinical conseuqences.
16 Immunogenicity to BiopharmaceuticalsB Limits efficacy for many biological therapeutics IgG antibodies can neutralize a therapeutic protein, IgG antibodies can block action of endogenous homolog IgE antibodies can cause anaphylaxis Poses ongoing concern for licensed products following changes in manufacture, packaging, and clinical indication
17 Erbitux CHARLOTTESVILLE, Va., March The unusual but severe allergic reactions to the cancer agent cetuximab (Erbitux), a monoclonal antibody, appear to be caused by preexisting immunoglobulin E (IgE) antibodies, researchers here found. The IgE antibody was specific for the sugar galactose-α-1,3 1,3-galactose expressed in the cell line used to produce cetuximab. The etiology may be tick bites and hypersensitive patients may be identifiable. The researchers tested blood samples from cetuximab-treated patients from three locations across the country as well as several control groups. The ImmunoCAP test captured antibodies that had bound to an antigen, which allowed the researchers to determine what kind of reaction was occurring. The assay did detect IgE antibodies as suspected, and more than 95% of these were bound to the Fab portion of the cetuximab heavy chain, where galactose-α- 1,3-galactose is found.
18 Expression System Affects Glycosylation Mammalian Cells CHO NS0 C127 Transgenic Animals Bacterial Fungi Yeast Insect Plant
19 Expression System Affects Glycosylation Bioequivalency of recombinantly engineered proteins is the most critical issue
20 Plant Glycosylation Challenges and Solutions Gomord and Faye 2004
21 Plant Glycosylation Challenges and Solutions MALDI-TOF mass spectra of glycans from Arabidopsis thaliana endogenous proteins A: Wild-type A. thaliana. B: XylT knockout (xylt). R. Strasser et al., FEBS Letters 561 (2004) 132 C: FucTA/FucTB double knockout (fuct). D: FucTA/FucTB/XylT triple knockout plants (xylt/fuct).
22 Plant Glycosylation Challenges and Solutions Down-regulated expression of plant-specific glycoepitopes in alfalfa through: Transformation with Human β-(1 4)Gal Transferase Gene Natural form and fusion with plant Golgi targeting domain Also, sirna silencing of XylT and FucT Overall result: Less β-(1 2)Xyl and α-(1 3)Fuc on glycoproteins which improves utility of alfalfa for recombinant use. Sourrouille et al, 2008, Plant Biotech. J., 6: ,
23 Plant Glycosylation Challenges and Solutions Physcomitrella patens engineered to reduce β-(1 2)Xyl and α-(1 3)Fuc (Koprivova 2004/Heuther 2005). Transient protoplast transformation with gene for hepo Authors demonstrated a maximum production of rhepo in XylT/FucT knockout plants at 144 hours Yield ~ 14 ng/ml Maximum yield was over twice that of same construct(s) in WT moss Weise et al, 2007, Plant Biotech. J., 5:
24 Biopharmaceutical Production in Plants Oil body targeting of recombinant human insulin in seeds. Oleosin-human pre-insulin fusion protein expressed in seeds of Arabidopsis Authors recovered insulin up to 0.13% w/w of transgenic seed protein Oil-body prepared protein was shown to be biologically active Nykiforuk et al, 2006, Plant Biotech. J., 4:77-85
25 Culture Conditions Affect Glycosylation
26 Culture Conditions Affect Glycosylation In vivo Activity of rherythropoeitin Obtained from different sources Hollow fiber reactor Roller bottle Fed-batch reactor In vivo Activity of rherythropoieitin in vivo % Sample Sample Yuen, C.T. et al., 2003
27 Batch-to-Batch Variation in glycosylation Gervai et al. (2003), Glycosylation of human recombinant gonadotrophins: characterization and batch-to-batch consistency. Glycobiology 13(3):
28 Antigenicity can differ for product from different manufacturing sites Antigenicity of identical rhifn- produced at different sites Schellekens ppt presentation Immunogenicity: The key issue for biosimilars
29 CAMBRIDGE, Mass., April 21 /PRNewswire-FirstCall/ -- Genzyme Corporation (Nasdaq: GENZ) announced today that the FDA has informed the company of its opinion that Myozyme(R) (alglucosidase alfa) produced at the 160L bioreactor scale and Myozyme produced at the 2000L scale should be classified as two different products because of differences in the carbohydrate structures of the molecules. Currently, Genzyme has U.S. approval to sell Myozyme manufactured at the 160L scale, and the company has been seeking clearance from the FDA for Myozyme produced at the 2000L scale. Production at this larger scale has already been approved in more than 40 countries. Myozyme is the only treatment for Pompe disease -- a severe, progressively debilitating and life-threatening inherited disorder affecting a very small number of people throughout the world.
30 Summary Glycosylation of Biopharma Drugs Can be affected by several factors: Host & expressions system Extracellular ph & buffer system NH4 accumulation CO2 accumulation Temperature Nutrient feeds Operating mode (batch vs. perfusion) Harvest times Agitator shear Bioreactor type Manufacturing Site
31 Library of Humanized Yeast Strains GFl 1.0 GFl 2.0 GFl 3.0 GFl 4.0 GFl 5.0 GFl 6.x6.0 GFl GFl 1.1 GFl 2.1 GFl 3.1 GFl 4.1 GFl 5.1 GFl 6.1 GFl 3.2 GFl 4.2 GFl 5.2 GFl 2.2 GFl 6.2 GFl 1.2 GFl 2.3 GFl 3.3 GFl 4.3 Choi et al., PNAS, 2003 Hamilton et al. Science, 2003 Bobrowicz et al., Glycobiology, 2004 GFl 4.4 Gerngross T.U.., Nature Biotechnology, 2004 Wildt and Gerngross, Nature Microbiology Reviews, 2005 GFl 5.3 GFl 5.4 GFl 6.3 GFl 6.4
32 Neose-GlycoAdvance improves Sialylation
33 Summary Need to overcome glycosylation challenges Better biochemical and molecular understanding of glycosylation process regulation This knowledge will help in engineering glycosylation pathways Better analytical tools for RAPID carbohydrate analysis Genome microarray and Glycan microarray analytical tools Better mathematical models to understand the complex interactions involved in controlling glycosylation Synthetic Glycobiology
34
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