Glycoproteins and Gal-GalNAc cause Cryptosporidium to switch ...
Associate professor Copenhagen Center for Glycomics ... · Copenhagen Center for Glycomics,...
Transcript of Associate professor Copenhagen Center for Glycomics ... · Copenhagen Center for Glycomics,...
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Hans H. Wandall, MD, PhDAssociate professor
Copenhagen Center for Glycomics, Department of Cellular and
Molecular Medicine
University of Copenhagen
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Polypeptide GalNAc-Transferases (GalNAc-Ts) in biology and medicine
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)
• Structure, enzymatic function, and complexity of the
large family of GalNAc-Ts
– Domain structure; kinetic activity; differential
expression
– A few words on model systems
• Search for the biological functions of GalNAc-Ts
– GlyMap
– Engineered cell models
• GalNAc-Ts – as a useful tool in translational research
– Discovery platforms for biomarkers, therapeutic
antibodies, and vaccines
– Development of novel production platforms for
human protein drugs
Polypeptide GalNAc-Transferases (GalNAc-Ts) in
biology and medicine
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)
Essentials of Glycobiology, 2nd ed., P. Stanley 2011
• 10% of all proteins
• 50% of proteins going through Golgi
All cells are covered with glycoconjugates
Mucin-type O-glycans
Dias 4
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Initiation of mammalian O-linked glycosylation
• Most O-linked genes non-redundant
• GalNAc-type genes partially redundant
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)
Mucin (GalNAc)-type protein O-glycosylation
Formation of complex O-GalNAc glycans with different core structures
GalNAca1-O-
20 genes
T
UDP-GalNAc
GalNAc-transferase
NH2
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)
mucin-type O-linked glycans
Distribution of unique glycan structures are differentially regulated
Tarp et al
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GalNAc-Ts basics
• Family of 20 GalNAc-Ts highly conserved throughout evolution;
existing in pairs/clusters
• Individual GalNAc-Ts have distinct peptide specificities, although
considerable overlap exist
• Acceptors include both unmodified and modified (GalNAc
glycosylated) substrates
• A C-terminal GalNAcT lectin domain modulates the specificity
toward partially glycosylated GalNAc peptide substrates
• GalNAc-Ts are differentially expressed in tissues, during
differentiation, and changes are seen in malignancies
UDP-GalNAc
GalNAca1-O-
20 genes
T
GalNAc-transferase
NH2
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)
T1 T2 T3
• Type II membrane structure (short N-terminal cytoplasmic tail,
hydrophobic membrane-spanning domain, stem region, catalytic
domain)
• Subcellular topology: Present throughout the Golgi with isoform-specific
differences
• Redistribution to ER during cellular activation (EGF-R, SrcKinase)
• Importance for glycosylation hierarchy inside cells?
Golgi localization of GalNAc-Ts
NH2
Further elongation
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)
• Expression profiling has demonstrated differential
expression in tissues and organs
• Creation of specific monoclonal antibodies has
confirmed these finding with differential
expression in tissues
-ex. T11/T14 in kidney
• Differential expression changes during
differentiation
- skin as an exemplar
GalNAc-Ts change expression during
differentiation and development
Diffe
rentiation &
matu
ration
T1 T2 T3
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Marked changes during cancer progression
• GalNAc-T2 (Liver: UP)
• GalNAc-T3 (Lung UP, Pancreas DOWN)
• GalNAc-T6 (Breast UP, Colon UP, Oral UP)
• GalNAc-T12 (Colon and gastric UP)
• GalNAc-T13 (High metastatic cell lines DOWN)
GalNAc-Ts change during malignant transformation
Illustration from Wandall et al 2007; Bennett et al. 2012
Normal
Oral Cancer
Normal
Oral Cancer
T3 T6
Normal Colon Cancer
T6 T6
Important information both for basic understanding as well as therapeutic and diagnostic applications?
Normal
Cancer
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Domain structures
The catalytic domain
• The GalNAc-T catalytic domains contain a GT-A
structural motif characterized by two tightly interacting
folds
– A conserved DxH Mn2+ ion binding motif
interacts with the donor substrate UDP
– A Gal/GalNAc-T motif interacts with the GalNAc
moiety
• A pre-formed channel in the surface of the catalytic
domain interacts with the acceptor substrate
• Random peptide and glycopeptide libraries have
revealed acceptor substrate preferences for GalNAc-T
isoforms – still difficult to predict (P +3)!
• Peptide versus Glycopeptide acceptors
Gerken et al. ; Bourne and Henrissat; Fritz et al.; Kubota et al. 2006; Wandall et al.2007; Pedersen et al. 2011; 2011, Bennett et al; Jill et al 2011
NH2
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�
Domain structures
The Lectin domain
• GalNAc-TFs contain a C-terminal lectin domain with a β-trefoil structure (three
repeats: α, β and γ)
• Lectin domain modulate and improve the catalytic efficiency of GalNAc-Ts
with incompleted GalNAc-substrates (mucins).
Gerken et al. ; Bourne and Henrissat; Fritz et al.; Kubota et al. 2006; Wandall et al.2007; Pedersen et al. 2011; 2011, Bennett et al; Jill et al 2011
NH2
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Single site and high density glycosylation
• Synthesis of mucins (multiple sites) covered by multiple GalNAc-Ts (redundant)
• Synthesis of single site covered by individual GalNAc-Ts (non-redundant) – how
do we identify their functions?
Further elongation
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Mouse models• Mice deficient in galnt4, t5, t4&t5, t8, or t14 have no overt phenotype
confirming the predicted redundancy.
• Loss of a single galnt gene may thus produce more discrete phenotypes in
select organs:
– Mice deficient in galnt1 exhibit a bleeding disorder and have deficiency
in B-cell maturation.
– Mice deficient in galnt13 exhibit decreased expression of Tn
carbohydrate in brain tissues, but no apparent phenotype.
– Mice deficient in galnt3 develop the classical familiar Tumor Calcinosis
(a heridetary disease with calcified masses).
• More detailed analysis required to decipher the subtle phenotypes
(Marth 1996; Lowe and Marth 2003; Tenno et al. 2007; Ten Hagen et al. 2002; Zhang et al. 2003; Tabak 2010; Manzi et al. 2000;
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Fly models
• Drosophila Melanogaster useful model system to identify
essential biological functions.
• Fly GalNAc-Ts are highly homologues enzymes with
preserved domain structure and enzymatic functions
• Studies in Drosophila melanogaster provided the first
demonstration that one member of this gene family
(pgant35A; GalNAc-T11 homologue) is essential for
viability
• pgant35A is important for the diffusion barrier formation
in the developing respiratory system
• Another member, pgant3, affect integrin-mediated cell
adhesion during Drosophila development by influencing
the secretion of an extracellular matrix protein
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Essentials of Glycobiology. 2nd edition.Varki A, Cummings RD, Esko JD, et al. 2009
How does O-linked glycans impinge on cellular function and
communication?
•Assembly of signaling molecules
•Modulation of cell-adhesion
•Protein trafficking
The complex nature of vertebrate GalNAc-TFs makes it difficult to dissect the molecular
mechanisms
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GalNAc-Ts; Teaching objectives
• Structure, enzymatic function, and complexity of the
large family of GalNAc-Ts
– Domain structure; kinetic activity; differential
expression
– A few words on model systems
• Search for the biological functions of GalNAc-Ts
– GlyMap
– Engineered cell models
• GalNAc-Ts – as a useful tool in translational research
– Discovery platforms for biomarkers, therapeutic
antibodies, and vaccines
– Development of novel production platforms for
human protein drugs
-
)
GalNAc-Ts basics
• Family of 20 GalNAc-Ts highly conserved throughout evolution;
existing in pairs/clusters
• Individual GalNAc-Ts have distinct peptide specificities, although
considerable overlap exist
• Acceptors include both unmodified and modified (GalNAc
glycosylated) substrates
• GalNAc-Ts are differentially expressed in tissues, during
differentiation, and changes are seen during malignant
development
UDP-GalNAc
GalNAca1-O-
20 genes
T
GalNAc-transferase
NH2
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)
Specific non-redundant functions of GalNAc-Ts
Dias 20
How does O-linked glycans impinge on cellular function and communication?
•Assembly of signaling molecules
•Modulation of cell-adhesion
•Protein trafficking
Mucin domains and clustered O-glycans
•Many biological functions
•Synthesis covered by multiple GalNAc-Ts (redundant)
Single or isolated O-glycans
•Functions?
•Synthesis covered by individual GalNAc-Ts (non/less-redundant)
How to identify isoform-specific non-redundant functions
Murine model, fly model, and human model?
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)
GALNT1
GALNT2
GALNT3
GALNT4
GALNT5
GALNT6
GALNT7
GALNT8
GALNT9
GALNT10
GALNT11
GALNT12
GALNT13
GALNT14
GALNT15
GALNT16
GALNT17
GALNT18
GALNT19
GALNT20
Familial Tumoral Calcinosis
HDL/TG dyslipidemia?
Newborn heart heterotaxy?
Trail drug sensitivity?
Colon cancer susceptibility
Sickle cell pulmonary complication?
Male infertility (immobile sperm)
B-cell immunity?
Elevated BMI?
GalNAca1-O-
20 genes
T
UDP-GalNAc
GalNAc-transferase
NH2
Disease/phenotype association of the 20
polypeptide GalNAc-Ts
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㜰�
Backtrack
Backtrack
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㜰�
Discovery of diseases of the glycogenome
• Diseases caused by non-global defects in glycosylation missed
• Strategies: GlyMAP and SimpleCells ~ Targeted Glycomics
GLYMAP
Map of mutations
with functional
consequences
SIMPLE CELLS
Cell lines
engineered to
analyze enzyme
function
Targeted Glycomics
(Copenhagen Center for Glycomics)
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The GlyMAP Strategy – Functional Mutational MAP
Exome sequence information of glycogenes from >2,000 persons
GlyMAPMap of functional mutations in population
Glycogene
Deleterious mutations
Discovery by genotyping select disease populations
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閐ʹ
Structural information is key: ZFN Engineered Isogenic Cell Lines
Steentoft et al. Nat. Methods 2011
Backtrack
Tn
STn
Core 1
Core 2
ST
C1GalT1
cosmc
Core 3
Core 4
a O-glycosylation pathway
GalNAc Galactose GlcNAc Sialic acid
ZFN targeting
COSMC–/–
+Neuraminidase
+Trypsin
VVA chromatography
Colo205
K562
Capan-1
SimpleCell Digest
nLCHCD-MS2
b and y ions
ETD-MS2
c and z ions
FT-MS1 and precursor selection
Time (min)
50 150100
Tota
l io
n c
urr
ent100
0
m/z
1,200800400
100
0
100
0
m/z
500 1,000 1,500 2,000
204.086
44.64
506 508
z = 4
Rela
tive a
bu
nd
an
ce
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閐ʹ
GALNT1
GALNT2
GALNT3
GALNT4
GALNT5
GALNT6
GALNT7
GALNT8
GALNT9
GALNT10
GALNT11
GALNT12
GALNT13
GALNT14
GALNT15
GALNT16
GALNT17
GALNT18
GALNT19
GALNT20
GWAS: HDL/Triglyceride dyslipidemia?
Example: Disease/phenotype association between T2
and changes in lipid metabolism
GalNAc-T2 regulates HDL-Cholsetrol
• Overexpression of GalNAc-T2 ⇒ HDL-Cholesterol↓
• Knock-down of GalNAc-T2 ⇒ HDL-Cholesterol↑
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Complex regulation of lipid metabolism
Modified from Willer Nat Gen 2008, News & Views
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閐ʹ
Example: GALNT2 and Dyslipidemia?
Candidate Disease Gene
GWASGALNT2 in lipid metabolism
+-.
......
Differential glycoproteome
m/z
nLC-MS/MS
-+SimpleCells +/- GALNT2
Biomarker
Wild type
GalNAc-T2 Tn
SimpleCells
+T2
-T2
+T2
-T2
HepG2 liver cells
Schjoldager et al. PNAS 2012
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잠;
Example: GALNT2 and Dyslipidemia?
Candidate Disease Gene
GWASGALNT2 in lipid metabolism
+-.
......
Differential glycoproteome
m/z
nLC-MS/MS
-+SimpleCells +/- GALNT2
Biomarker/Function
Probing isoform-specific functions of GalNAc-Ts
VVA
chromatography
nLC-MS/MS
Schjoldager et al. PNAS 2012
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잠;
Complex regulation of lipid metabolism
Modified from Willer Nat Gen 2008, News & Views
APO CIII; protein
component of VLDL
(very low density
lipoprotein).
Angiopoietin-
like 3 (ANGPTL3)
is a determinant
factor of HDL
level
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ᢐҘ
Biomarker for GALNT2 Deficiency – ApoC-III
10 Glycosylated
ApoC-IIIStd
HepG2
WT -T2 +T2 -T1
Non-Glycosylated
Human serum (1 uL)
#1 #2 #3
ApoC-III SDS-PAGE WB
Schjoldager et al. PNAS 2012
Loss of GalNAc-T2 glycosylation of ApoC-III could be used as biomarkers and
may point to the molecular explanation of GalNAc-T2 involvement in HDL
metabolism
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߰ͻ
ANGPTL3 is specifically glycosylated by GalNAc-T2
Proprotein convertase
(Furin)
(Activates)
GalNAc-T2
Angiopoietin-like 3 (ANGPTL3)
•Secreted factor produced in the liver
•In humans, ANGPTL3 is positively correlated with
plasma HDL cholesterol
Loss of GalNAc-T2 glycosylation of ANGPTL3 would increase cleavage and
release of ANGPTL3 positively correlated with plasma HDL levels
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��
Perspectives – An Example (GALNT2)
Candidate Disease Gene
GWASGALNT2 in lipid metabolism
Exome sequence variants
Functional mutations in population
Genotyping
PatientMolecular mechanism
-+SimpleCells +/- GALNT2
+-.
......
Differential glycoproteome
APO-CIII
Disease mechanism/Biomarker
m/z
nLC-MS/MS
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߰ͻ
GALNT1
GALNT2
GALNT3
GALNT4
GALNT5
GALNT6
GALNT7
GALNT8
GALNT9
GALNT10
GALNT11
GALNT12
GALNT13
GALNT14
GALNT15
GALNT16
GALNT17
GALNT18
GALNT19
GALNT20
HDL/TriGlyceride dyslipidemia?
Example: Disease/phenotype association of the 20
polypeptide GalNAc-Ts for O-glycosylation
Familiar Calcinosis and T3
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߰ͻ
GALNT3 and FTC – another example of essential
co-regulation of PC processing
• Familial tumoral calcinosis (FTC)
• Hyperphosphatemia
• Calcium deposits and ossifications
• Caused by loss of FGF23
• FGF23 is responsible for phosphate metabolism
• PC processing inactivates FGF23
• Lack of GalNAc-T3 glycosylation cause inactivation
of FGF23
Topaz et al., Nat. Genet., 2004. Kato et al., JBC, 2006. Benét-Pages et al., Hum. Mol. Genet., 2005
Proprotein convertase (furin)
T3-/-
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߰ͻ
GalNAc O-glycosylation modifies PC processing
•Assembly of signaling molecules
•Modulation of cell-adhesion
•Protein trafficking
•Differentiation
•Pro-Protein processing
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ꃠͺ
GalNAc-Ts; Teaching objectives
• Structure, enzymatic function, and complexity of the
large family of GalNAc-Ts
– Domain structure; kinetic activity; differential
expression
– Model systems
• Search for the biological functions of GalNAc-Ts
– Specific and redundant functions
– Engineered cell models
• GalNAc-Ts – as a useful tool in translational research
– Discovery platforms for biomarkers, therapeutic
antibodies, and vaccines
– Development of novel production platforms for
human protein drugs
-
ꃠͺ
GalNAc-Ts – as a useful tool in translational research
• Discovery platforms for biomarkers:
Autoantibodies and tumor specific
products
• Cancer specific antibodies and chemo-
enzymatic creation of antigens for cancer
vaccines
• Enzymatic modification of protein drugs for
improvement of pharmacokinetic properties
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)
Glyco-challenges in cancer detection and treatment
Healthy
Premalignant
Stage I
Stage II
Stage III
Stage IV
• Surgical
• Chemotherapy
• Biological treatment
• Immunotherapy (?)
Active and passive
Early detection Treatment
Clinical diagnosisS
urv
ival
Breast cancer
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ꃠͺ
Glycan changes during cancer development
Healthy
Premalignant
Stage I
Stage II
Stage III
Stage IV
Surface carbohydrates
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ꃠͺ
Cancer associated changes:
• Truncated glycans
• Increased sialyation
• Altered glycosylation densitiy
• Molecular background:
- Disruption of the secretory pathway, pH change
- Down regulation or mutations in glycosyltransferases
and chaperones
Cancer associated mucin-type O-linked glycans
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ꃠͺ
Fig: Sørensen et al., 2012
• Current serological cancer markers are tumor products:
proteins (PSA, CA125)
Limitations:
• Vanishing small amounts produced with short serum half
life
• Proteins carrying cancer associated glycans selectively
cleared by carbohydrate receptors
• Remaining circulating proteins carry glycans resembling
glycans on proteins from non-malignant cells
Diagnostic implications:
How does cancer associated glycans impact biomarker discovery?
Stage I
Stage II
Stage III
Stage IV
Su
rviva
l
Pre-
malignant
Wahrenbrock MG, Varki A, Canc. Res., 2006; Wandall et al., Canc.Res. 2010
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ꃠͺ
Selective clearance of cancer associated glycans
– autoantibodies as an alternative?
Wandall et al., Canc.Res., 2010
• Auto-antibodies could be used as amplified signals for the
presence of cancer
• Auto-antibodies appears years prior clinical appearance (p53).
• Mostly nuclear and cytoplasmic proteins identified to date with
High throughput methods: phage-display, recombinant cDNA
expression cloning (SEREX), peptide and protein arrays, and
self-assembling protein arrays.
• Change in PTMs induces presentation of specific targets to the
immune system
Stage I
Stage II
Stage III
Stage IV
Su
rviva
l
Pre-
malignant
Clinical
diagnosis
p53-Auto
antibodies
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ꃠͺ
Autologous immuneresponse to proteins carrying
cancer associated glycoforms
Tolerance
Surface/SecretedGolgiER
Glycopeptide antibodies specific for cancer cells?
Clearance/Dendritic cell uptake via MGL et al.
Napoletano et al., 2007; Madsen et al, 2012, Van Kooyk
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ꃠͺ
Creation of the discovery platform: Mucin glycopeptide microarray
Serum ab
Anti-IgG
Glycopeptide
antigenCore 3 synthase
ST6GalNAc-I
Core 1 synthase
Tn ppGalNAc-Ts
T
Core 3
STn
Pedersen et al. Int J. Cancer, 2010
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ꃠͺ
Creation of the discovery platform: Mucin glycopeptide microarray
Serum ab
Anti-IgG
Glycopeptide
antigenCore 3 synthase
ST6GalNAc-I
Core 1 synthase
Tn ppGalNAc-Ts
T
Core 3
STn
Pedersen et al. Int J. Cancer, 2010
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ꃠͺ
• >100 Tandem repeats carrying O-linked glycans
• Over-expressed by common cancers
MUC1 carry aberrant glycans in cancer
Core 3 synthase
ST6GalNAc-I
Core 1 synthase
Tn ppGalNAc-Ts
T
Core 3
STn
Serum ab
Anti-IgG
Glycopeptide
antigen
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ꃠͺ
MUC1 STn
Con
trols
CRC
0
20000
40000
60000
80000
2SD3SD
RFU
MUC1 Core3
Con
trols
CRC
0
20000
40000
60000
80000
2SD3SD
RFU
MUC1
Con
trols
CRC
0
10000
20000
30000
40000
RFU
MUC1 Tn
Con
trols
CRC
0
20000
40000
60000
RFU
VTSAPDTRPAPGSTAPPAHG x 3MUC1 VTSAPDTRPAPGSTAPPAHG x 3MUC1 15TnMUC1 15Core3MUC1 15STn
6.9% 30% 33%57%
IgG auto-antibodies to MUC1 glycopeptides
• ~ 50% of colorectal cancer patients have auto-antibodies to MUC1 Glycopeptides.
Pedersen et al. Int J. Cancer, 2010
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隠ҕ
Autoantibodies in cancer:
Diagnostic and Therapeutic perspectives?
Autoantibodies
Selection of targets
Targets used for
production of selective
mAbs
Targets potential
candidates for active
vaccines
• Change in PTMs present specific SURFACE targets to the immune system
-
隠ҕ
• Specific targeting of cancer cells
• Breaking tolerance - providing danger signal to APC cells that
leads to enhanced T-cell activation
• Presentation to CD8+ AND CD4+ T-cells
Challenges in immunotherapy
What about antibodies?
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ꃠͺ
Louis M Weiner, Madhav V Dhodapkar, Soldano Ferrone. Lancet, 2009
Antibody responses
Antibodies can stimulate antigen specific immune responses trough:
1.Antibody-dependent cellular cytotoxicity
2.Promotion of antibody-targeted cross-presentation of tumor antigens
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)
Could carbohydrate antigens be targeted – challenges and
possibilities?
• Carbohydrates are often poorly immunogenic.
• Carbohydrate-specific antibodies have low affinity compared with protein-specific antibodies
• Heterogeneous display of glycans on target cells dilute the effect
• NEED FOR MORE THAN JUST SUGARS – Glycopeptides?
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黰ҕ
• >100 Tandem repeats carrying O-linked glycans
• Over-expressed by common cancers
MUC1 carry aberrant glycans in cancer
Autoantibodies
Selection of targets
Targets used for
production of
selective mAbs
Targets potential
candidates for
active vaccines
MUC1 HMFG2
IgG auto-antibodies to MUC1 glycopeptides
Tn-MUC1 5E5
Burchel et al.; Sørensen et al,2006
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)
Breast cancer express the 5E5 epitope
Breast cancer Normal Breast Lactating breast
Tn-MUC1
MUC1 HMFG2
5E5
Lavrsen et al. 2012
• Tn-MUC1 epitope is selectively expressed in
breast cancer tissue
• 5E5 has high affinity to Tn-MUC1 (Kd 1.7 nM)
• 5E5 mediate ADCC of breast cancer cell lines
-
齀ҕ
-KLH
• Pilot Phase I study: Subcutanous delivery Tn-106merMUC1-KLH (20 high-risk
breast cancer patients immunized x 3)
• 19 patients developed significant anti Tn-MUC1 IgG antibody titers
• Tn-MUC1 induced immune response mimics reactivity of mAb 5E5
• Increase in ADCC in 3 out of 17 patients associated with “no evidence of
disease” (3/5)
0
1
2
3
Pre-vaccination serum samples
0
1
2
3
Post-vaccination serum samples
Pre-Immunization Post-Immunization
5E5 epitope
Wandall et al, Cancer Research, 2009
Active immunotherapy: Tn-MUC1 overrides tolerance in humans
5E5 like response
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)
• GalNAc conjugated to larger molecules demonstrated to increase uptake and
promote both CD4 and CD8 responses
• Position of GalNAc(s) is critical for processing and hence CD8 responses
• GalNAc-MUC1 with 1 (one) GalNAc in SAPDT(GalNAc)RPAPG as fusion molecules
with TLR9 helper sequences demonstrates both CD4 and CD8 GalNAc-peptide
specific response
Glycans help uptake and induce cross presentation
Boons and Gendler et al., Kooyk et al.; Madsen et al.
-
龐ҕ
Fig: Sørensen et al., 2012
• Protein drugs often have short serum half life
• Proteins carrying truncated glycans are selectively cleared by carbohydrate receptors
• Human Granulocyte Colony Stimulating Factor (hGCSF) for the treatment of leukemia
as an example.
How to improve circulation time of protein drugs?
Wahrenbrock MG, Varki A, Canc. Res., 2006; Wandall et al., Canc.Res. 2010
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)
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• Covalent attachment of PEG prolongs the half-life and enhance the
pharmacodynamics of therapeutic proteins
• Methods for PEGylation largely rely on chemical conjugation which often
interferes with bioactivity
• GalNAc-TFs presents a novel strategy for site-directed PEGylation attaching
PEG to O-glycans – example human Granulocyte Colony Stimulating Factor
(hGCSF) for the treatment of leukemia
• Enzymatic GalNAc glycosylation at specific serine and threonine residues in
proteins expressed in Escherichia coli, followed by enzymatic transfer of sialic
acid conjugated with PEG to the introduced GalNAc residues
The use of GalNAc-TFs for site-directed modification of human
protein drugs
-
�ҕ
Teaching objectives
• Structure, enzymatic function, and complexity of the
large family of GalNAc-Ts
– Domain structure; kinetic activity; differential
expression
– Model systems
• Search for the biological functions of GalNAc-Ts
– GlyMap
– Engineered cell models
• GalNAc-Ts – as a useful tool in translational research
– Discovery platforms for biomarkers, therapeutic
antibodies, and vaccines
– Development of novel production platforms for
human protein drugs
-
)
Financial support U. of Copenhagen
Danish Research Councils
The Carlsberg Foundation
The Alfred Benzons Foundation
The AP Møller Foundation
The Lundbeck Foundation
EU FP7, EU Marie Curie
NIH-NCI
Yun Kong
Christoffer Goth
Stjepan Kracun
Kowa Chen
Catharina Steentoft
Kirstine Lavrsen
Sarah King Smith
Caroline Benedicte Madsen
Catharina Steentoft
Lara Da Silva
Diana Campos
Rikke Svava
Henrik Clausen
Eric Bennett
Ulla Mandel
Hans Wandall
Ola Blixt
Sergey Vakhrushev
Steven Levery
Malene Vester-Christensen
Nis Borbye Pedersen
Zhang Yang
Yoshiki Narimatsu
Hiren Josh
Katrine Schjoldager
Johannes W. Pedersen
Thank you!
Special thx to Katrine Schjoldager& Eric P.
Bennettfor slide support