In Partnership with: Biopharmaceuticals and Glycosylation Biopharmaceuticals and Glycosylation ABIC, Cork, Ireland August 27 2008 Lokesh Joshi Stokes Professor of Glycosciences Associate Director, Center for BioAnalytical Sciences National University of Ireland Galway
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In Partnership with:
Biopharmaceuticals and GlycosylationBiopharmaceuticals and Glycosylation
ABIC, Cork, Ireland
August 27 2008
Lokesh JoshiStokes Professor of Glycosciences
Associate Director, Center for BioAnalytical SciencesNational University of Ireland Galway
The Market For Glycoprotein DrugsThe Market For Glycoprotein Drugs
Most Biopharmaproteins Induce AntibodiesMost Biopharmaproteins Induce Antibodies
Current analytical methods cannot fully predictbiological properties.
The immune system can detect alterations inproducts missed by analytical methdos.
Immunogenicity to the biopharmaceuticals mayhave serious clinical conseuqences.
Immunogenicity to BImmunogenicity to Biopharmaceuticalsiopharmaceuticals
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 productsfollowing changes in manufacture, packaging, andclinical indication
CHARLOTTESVILLE, Va., March 12 2008 -- The unusual but severe allergicreactions to the cancer agent cetuximab (Erbitux), a monoclonal antibody,appear to be caused by preexisting immunoglobulin E (IgE) antibodies,researchers here found.
TheThe IgEIgE antibody was specific for the sugar galactoseantibody was specific for the sugar galactose--αα--1,31,3--galactose expressedgalactose expressedin the cell line used to producein the cell line used to produce cetuximabcetuximab.. The etiology may be tick bites andhypersensitive patients may be identifiable.
The researchers tested blood samples from cetuximab-treated patients from threelocations across the country as well as several control groups. The ImmunoCAPtest captured antibodies that had bound to an antigen, which allowed theresearchers to determine what kind of reaction was occurring.
The assay did detect IgE antibodies as suspected, and more than 95% of thesewere bound to the FabFab portionportion of the cetuximab heavy chain, where galactose-α-1,3-galactose is found.
ErbituxErbitux
Expression System AffectsExpression System AffectsGlycosylationGlycosylation
Mammalian Cells CHO
NS0
C127
Transgenic Animals
Bacterial
Fungi
Yeast
Insect
Plant
Expression System AffectsExpression System AffectsGlycosylationGlycosylation
Bioequivalency ofrecombinantlyengineeredproteins is themost criticalissue
Gomord and Faye 2004
Plant Glycosylation Challenges and Solutions
MALDI-TOF mass spectra of glycans from Arabidopsisthaliana endogenous proteins
BatchBatch--toto--Batch Variation in glycosylationBatch Variation in glycosylation
Gervai et al. (2003), Glycosylation of human recombinant gonadotrophins:characterization and batch-to-batch consistency. Glycobiology 13(3): 179-189.
Antigenicity can differ for productAntigenicity can differ for productfrom different manufacturingfrom different manufacturing sitessites
Schellekens – ppt presentation “Immunogenicity: The key issue for biosimilars”
Antigenicity ofidentical rhIFN-produced at differentsites
CAMBRIDGE, Mass., April 21 /PRNewswire-FirstCall/ -- Genzyme Corporation
(Nasdaq: GENZ) announced today that the FDA has informed the company of itsFDA has informed the company of its
opinion thatopinion that Myozyme(RMyozyme(R) () (alglucosidasealglucosidase alfaalfa) produced at the 160L bioreactor scale) produced at the 160L bioreactor scale
andand MyozymeMyozyme produced at the 2000L scale should be classified as two differeproduced at the 2000L scale should be classified as two differentnt
products because of differences in the carbohydrate structures oproducts because of differences in the carbohydrate structures of the molecules.f 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.
Host & expressionssystem
Extracellular pH & buffersystem
NH4 accumulation
CO2 accumulation
Temperature
Nutrient feeds
Operating mode (batchvs. perfusion)
Harvest times
Agitator shear
Bioreactor type
Manufacturing Site
Glycosylation of Biopharma DrugsGlycosylation of Biopharma DrugsCan be affected by several factors:Can be affected by several factors:
SummarySummary
GFl 1.0
Library of Humanized Yeast Strains
GFl 2.0 GFl 3.0 GFl 4.0 GFl 5.0 GFl 6.0
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 5.2GFl 6.2
GFl 3.3 GFl 4.3 GFl 5.3 GFl 6.3
GFl 4.4 GFl 5.4 GFl 6.4
GFl 1.2GFl 2.2
GFl 2.3
GFl 6.x
Choi et al., PNAS, 2003Hamilton et al. Science, 2003Bobrowicz et al., Glycobiology, 2004Gerngross T.U.., Nature Biotechnology, 2004Wildt and Gerngross, Nature Microbiology Reviews, 2005