BLOOD.CA BLOOD.CA Canadian Blood Services it’s in you to give Mark D. Scott.
-
Upload
mark-williamson -
Category
Documents
-
view
223 -
download
4
Transcript of BLOOD.CA BLOOD.CA Canadian Blood Services it’s in you to give Mark D. Scott.
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 1
Immunocamouflage (Immunocamouflage (PEGylationPEGylation) ) of Red Blood Cellsof Red Blood Cells
The Canadian Blood ServicesThe Canadian Blood ServicesUniversity of British ColumbiaUniversity of British Columbia
Center for Blood Research & Department of Pathology & Laboratory Medicine
The Canadian Blood ServicesThe Canadian Blood ServicesUniversity of British ColumbiaUniversity of British Columbia
Center for Blood Research & Department of Pathology & Laboratory Medicine
Mark D. Scott, Ph.D.Mark D. Scott, Ph.D.Senior Scientist & Clinical ProfessorSenior Scientist & Clinical Professor
Associate Director, Intellectual Property and Business DevelopmentAssociate Director, Intellectual Property and Business Development
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 2
Red Blood CellsRed Blood Cells PlateletsPlatelets White Blood CellsWhite Blood Cells CollectionCollection DistributionDistributionSupplySupply
Red Blood CellsRed Blood Cells PlateletsPlatelets White Blood CellsWhite Blood Cells CollectionCollection DistributionDistributionSupplySupply
RBC PROBLEMS:RBC PROBLEMS: Lack of O- Blood, Alloimmunization, Shelf-Life, Cost of
Production, Cost of Distribution
RBC PROBLEMS:RBC PROBLEMS: Lack of O- Blood, Alloimmunization, Shelf-Life, Cost of
Production, Cost of Distribution
Canadian Blood Service
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 3
The Holy GrailThe Holy Grail
Don’t need (as many) donors!
No Blood Groups - carefree…!
Long shelf life - months...!
Solving the Problems of Traditional Blood Products
BloodBlood Substitutes!BloodBlood Substitutes!
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 4
““Blood SubstitutesBlood Substitutes””
• • PerflurocarbonsPerflurocarbons• • PerflurocarbonsPerflurocarbons1980s-1990s1980s-1990s
• Complement Activation• Vascular Leakage• Other RBC Functions?
• Complement Activation• Vascular Leakage• Other RBC Functions?
XX
• • Purified Purified HemoglobinsHemoglobins
Free & Liposome EncapsulatedFree & Liposome Encapsulated
• • Purified Purified HemoglobinsHemoglobins
Free & Liposome EncapsulatedFree & Liposome Encapsulated
1980s-2000s1980s-2000s
What Does The Holy Grail
Look Like?
• Toxicity• Small Size• Vascular Leakage• Tissue Iron Loading• Other RBC Functions?
• Toxicity• Small Size• Vascular Leakage• Tissue Iron Loading• Other RBC Functions?
XX
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 5
A Brief History of Hb-Based A Brief History of Hb-Based Blood SubstitutesBlood Substitutes
1980 - 20081980 - 2008
1980s:1980s: US Military BEGINS massive (and expensive) research program to develop hemoglobin (Hb) based blood substitutes. Numerous private companies (e.g., Somatogen, Baxter, HemosolHemosol, Northfield, BioPure) begin commercialization of yeast-produced, human and bovine based Hb-based blood substitutes.
1990s:1990s: US Military STOPS massive (and expensive) research program to develop Hb-based blood substitutes. Private companies “soldier on” trying to produce a safe and commercially viable product. Many fail or abandon development (e.g., Somatogen and Baxter).
2000s:2000s: Despite two decades of commercial (e.g., HemosolHemosol ) and clinical trial failures, a few companies persist in development of Hb-based blood substitutes (Sangart, Northfield and BioPure). Commercial success and product safety remain uncertain.
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 6
030303 $288.00
090224090224 $0.08$0.08
BioPureBioPure (BPUR)(BPUR)
Hemopure:Hemopure: approved for sale in South Africa for surgical patients, anemic patients, and for eliminating, delaying, or reducing allogenic red blood cell transfusions in these patients. [Problems with repeated dosing....]
Oxyglobin:Oxyglobin: oxygen therapeutic approved by the US FDA and the European Commission for the treatment of anemia in dogs. The Company has sold ~182,000 units of Oxyglobin since approval.
Produces BOVINEBOVINE sourced HemopureHemopure (human
use) and OxyglobinOxyglobin (veterinary use).
Produces BOVINEBOVINE sourced HemopureHemopure (human
use) and OxyglobinOxyglobin (veterinary use).
Cost to transfuse a “YellowYellow” Lab once*:
~$1000.00
Cost to transfuse a “YellowYellow” Lab once*:
~$1000.00
*At the recommended dosage
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 7
So Why Does Purified Hemoglobin Fail?So Why Does Purified Hemoglobin Fail?The job of blood is to deliver Oxygen to the tissues...
purified hemoglobin does this badly!
Vasoconstriction is just ONE of the
multitude of problems associated with
purified hemoglobin solutions!
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 8
In General, In General, “Blood Substitutes”“Blood Substitutes” Have Been Have Been A Major DisappointmentA Major Disappointment
In General, In General, “Blood Substitutes”“Blood Substitutes” Have Been Have Been A Major DisappointmentA Major Disappointment
“Hemoglobin shall be INSIDE red blood cells…” “except, of course,
in earthworms.”
“Hemoglobin shall be INSIDE red blood cells…” “except, of course,
in earthworms.”
The Book of Darwin: Chapter 14, Verse 8
The Book of Darwin: Chapter 14, Verse 8
However, Darwin’s teachings requires However, Darwin’s teachings requires that the that the inherent antigenicity inherent antigenicity and and
immunogenicity immunogenicity of the RBC be tamed.of the RBC be tamed.
However, Darwin’s teachings requires However, Darwin’s teachings requires that the that the inherent antigenicity inherent antigenicity and and
immunogenicity immunogenicity of the RBC be tamed.of the RBC be tamed.
Perhaps DarwinDarwin Has A Point!
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 9
““Blood - It’s In You To GiveBlood - It’s In You To Give®®””®®Canadian Blood ServicesCanadian Blood Services
Purified Purified HemoglobinsHemoglobins
Free & Liposome EncapsulatedFree & Liposome Encapsulated
Purified Purified HemoglobinsHemoglobins
Free & Liposome EncapsulatedFree & Liposome Encapsulated
PerflurocarbonsPerflurocarbonsPerflurocarbonsPerflurocarbons
ImmunocamoulfagedImmunocamoulfaged RBCRBC
Taming the Taming the inherent antigenicityinherent antigenicity and and immunogenicity immunogenicity of the RBC.of the RBC.
Meeting Darwin’s Requirements....Meeting Darwin’s Requirements....
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 10
Since the mid-1970’s Since the mid-1970’s methoxypoly(ethylene glycol) methoxypoly(ethylene glycol) [mPEG] [mPEG] has has been “glued” to proteins to prolong circulation and prevent immune been “glued” to proteins to prolong circulation and prevent immune recognition. recognition. PEGylated enzymes are currently used for the clinical PEGylated enzymes are currently used for the clinical
treatment of enzymopathies.treatment of enzymopathies.
Immunocamouflage of CellsImmunocamouflage of Cells
My Laboratory Pioneered The
Immunocamouflage of Intact Cells
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 11
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 02/2009
CarbowaxCarbowax®®
In 1927 In 1927 Prestone Prestone introduced introduced Ethylene Ethylene GlycolGlycol** and the era of modern automotive and the era of modern automotive
antifreeze begunantifreeze begun ((thus saving modern Canadathus saving modern Canada).). **replacing such things as molasses, honey and methyl alcohol.replacing such things as molasses, honey and methyl alcohol.
Poly(Poly(ethylene glycolethylene glycol)) is repeating units of is repeating units of
automobile antifreeze!automobile antifreeze!
In 1927 In 1927 Prestone Prestone introduced introduced Ethylene Ethylene GlycolGlycol** and the era of modern automotive and the era of modern automotive
antifreeze begunantifreeze begun ((thus saving modern Canadathus saving modern Canada).). **replacing such things as molasses, honey and methyl alcohol.replacing such things as molasses, honey and methyl alcohol.
Poly(Poly(ethylene glycolethylene glycol)) is repeating units of is repeating units of
automobile antifreeze!automobile antifreeze!
Poly(Poly(Ethylene GlycolEthylene Glycol))Poly(Poly(Ethylene GlycolEthylene Glycol))Carbide and Carbin Chemicals Carbide and Carbin Chemicals Corporation (Union Carbide)Corporation (Union Carbide)
?! That can’t be ?! That can’t be safe!?safe!??! That can’t be ?! That can’t be safe!?safe!?
( )n
C C C OHHO
H
HH
H H H
HH
OC
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 12
Is PEG Safe?Is PEG Safe?By chemically linking several By chemically linking several ethylene glycolethylene glycol monomersmonomers
togethertogether,, a a non-toxic polymernon-toxic polymer [ [i.e.,i.e., Poly(ethylene glycol)Poly(ethylene glycol)]] is is produced that is commonly used in produced that is commonly used in modern medicine.modern medicine.
DeadlyDeadlyDeadlyDeadlySafeSafeSafeSafe
SafeSafeSafeSafeAt very HIGH levels, PEG oral toxicityoral toxicity arises due to GI “flow” effects…
Oral Rat LDOral Rat LD5050 for: for: Monomer 4.7 gm/kgPEG 200: 28 gm/kgPEG 1450: 40 gm/kgPEG 4000: >50 gm/kg
Oral Rat LDOral Rat LD5050 for: for: Monomer 4.7 gm/kgPEG 200: 28 gm/kgPEG 1450: 40 gm/kgPEG 4000: >50 gm/kg
~ 4 kg for me...
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 13
PEG: PEG: Safe and Non-ToxicSafe and Non-ToxicShaffer, C., Critchfield, F. The absorption and excretion of the solid polyethylene glycols
("Carbowax" compounds). Journal of the American Pharmaceutical Association 36:152-157; 19471947.
Smyth, H.; Carpenter, C., Shaffer, C. The toxicity of high molecular weight polyethylene glycols; chronic oral and parental administration. Journal of the American Pharmaceutical Association 36:157-160; 19471947.
ORALORAL (10 g bolus):(10 g bolus):
Safe. No measurable absorption from gut, but at high concentrations this industrial “lubricant” did cause diarrhea.
INJECTIONINJECTION (1 g in 20 ml):(1 g in 20 ml):
Safe. ~90% of PEG excreted by kidneys within 12 hours.““Gim’me da Gim’me da carbocarbo or I’ll or I’ll wax wax ya.”ya.”
19471947
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 14
Adhesives Agriculture Ceramics
CosmeticsCosmetics and Personal CarePersonal Care Electronics
ElectroplatingElectropolishing
FoodFood Processing
Household Products
Lubricants Metalworking
Paints and Coatings Paper and Paper Products
PharmaceuticalsPharmaceuticals Printing and Inks
RubberElastomers
Textiles Wood Treating
PEGPEGIndustrial-Medical-Consumer ApplicationsIndustrial-Medical-Consumer Applications
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 15
How Does PEG WorkHow Does PEG WorkHow Does PEG WorkHow Does PEG WorkPEG is a water-soluble, nontoxic, low immunogenicity polymer readily cleared from the body. Approved for oral, intravenous,
intramuscular, subcutaneous and topical administration.
( )n
C C C OHHO
H
HH
H H H
HH
OC
Physically creating a
semi-dense cloud above
the cell surface
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 16
How Does PEG WorkHow Does PEG WorkHow Does PEG WorkHow Does PEG WorkPEG is a water-soluble, nontoxic, low immunogenicity polymer readily cleared from the body. Approved for oral, intravenous,
intramuscular, subcutaneous and topical administration.
( )n
C C C OHHO
H
HH
H H H
HH
OC
Physically creating a
semi-dense cloud above
the cell surface
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 17
Immunocamouflage of CellsImmunocamouflage of CellsImmunocamouflage of CellsImmunocamouflage of Cells
BLOOD
TISSUES
SNOTSNOT
Hiding the Hiding the “Weapons of Mass Destruction”“Weapons of Mass Destruction” in in TransfusionTransfusion, , TransplantationTransplantation, and , and Family MedicineFamily Medicine
Hiding the Hiding the “Weapons of Mass Destruction”“Weapons of Mass Destruction” in in TransfusionTransfusion, , TransplantationTransplantation, and , and Family MedicineFamily Medicine
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 18
RBC Structure, RBC Structure, Function, and In Vivo Function, and In Vivo
Survival?Survival?
Do mPEG-RBC “Work”....
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 19
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 03/2009
Stealth Erythrocyte Are Stealth Erythrocyte Are NORMALNORMAL......
25
Lysi
sLy
sis
Grafting Process Does NOT Harm The RBC (<1% Lysis)
Normal Human RBC ParametersPEGylated Murine RBC Exhibit Normal In Vivo Survival
or at least appear to be normal...or at least appear to be normal...
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 20
Biophysical Effects of Biophysical Effects of mPEG GraftingmPEG Grafting
How Does the grafted mPEG
“Work”....
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 21
STEALTH CELLS - Charge CamouflageSTEALTH CELLS - Charge CamouflageSTEALTH CELLS - Charge CamouflageSTEALTH CELLS - Charge Camouflage
Modified from: Scott, M.D. et al. (2000)
Transfusion Medicine Reviews, 14:53-63.
Cell Charge Plays An
Important Role In Immune
Recognition.
Cell Charge Plays An
Important Role In Immune
Recognition.
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 22
Cell-Cell Interaction: Erythrocyte SedimentationCell-Cell Interaction: Erythrocyte Sedimentation
Modified From: Bradley, A.J. et al. (2002)
Biochimica et Biophysica Acta, 1561:147-58.
0
5
10
15
20
25
30
35
0 1 2 3 4 5 6
5 mM4 mM3 mM2 mM1.2 mM
0.6 mM
0 mM
Untreated
BTC-mPEG 20 kDa
Hours
Ery
thro
cyte
Sed
imen
tati
on R
ate
(mm
)
RBC Specific Gravity RBC Specific Gravity = = 1.0951.095
Plasma Specific Gravity Plasma Specific Gravity = = 1.0311.031
Rouleaux FormationRouleaux Formation
ControlControl
mPEG-RBCmPEG-RBC
Charge MediatedCharge Mediated
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 23
Cell-Protein Interaction: Decreased Fluorescent Fluorescent ProteinProtein Adsorption to Bare or mPEG-Modified
Latex Particles (8 µm).
20 kDa SVA-mPEGBare Latex
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 24
Decreased Low Shear Viscosity: Decreased Low Shear Viscosity: Utilization For Vascular Utilization For Vascular Occlusive Diseases (e.g., SCD)?Occlusive Diseases (e.g., SCD)?
Like SyrupLike Syrup
BadBadLike Water Like Water
GoodGood
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 25
Immunocamouflage of theImmunocamouflage of the
Rh Blood Group AntigensRh Blood Group AntigensThe Rh antigen family
is located at the membrane surface
does NOT extend very far out.
RhD – making the
“Near” Universal RBC
10 nm
10 nm
20 nm
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 26
Mea
n C
ell
Flo
resc
ence
Polymer Grafting Effectively Polymer Grafting Effectively Attenuates Antibody Attenuates Antibody Recognition of RhcRecognition of Rhc
Reducing The Risk Of Alloimmunization Reducing The Risk Of Alloimmunization (Rh Family)(Rh Family)
BLOOD GROUP ANTIGEN Percent Immuno-
genicity¢
Hemolytic
Trans. ReactionPrimary Ab
ABOABO A,BA,B 100100ªª YesYes IgMIgM
Rh D 50.00 Yes IgG
c 2.05 Yes IgG
E 1.69 Yes IgG
e 0.56 Yes IgG
C 0.11 Yes IgG
Kidd Jka 0.07 Yes IgG
Jkb 0.03 Yes IgG
Duffy Fya 0.23 Yes IgG
Kell k 1.50 Yes IgG
K 5.00 Yes IgG
MNS S 0.04 Yes IgG
s 0.03 Yes IgG
Single Exposure Risk of AlloimmunizationDerived from “Clinical Experimentation”
2% Risk
??% Risk
¢ Chance of AlloimmunizationFollowing Each Antigen Positive
Transfusion In A Null Individual
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 27
Immunocamouflaged of RhDImmunocamouflaged of RhD
Control 0.6 mM
1.2 mM 2.4 mM
5 mM
Agglutination Test for
RhDRhD
O+, O-, A+, A-, B+, B-, AB+, AB-
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 28
Is PEGylated RhD Immunogenic?RhD Allorecognition Using RhD- Antigen Presenting Cell (APC;
Dendritic-Like Cells) Cultures.
ImmatureDC-Like
5
Days
IL-4GM-CSF
Plasma
PBMC
Ficoll-Hypaque
RBC
(5hrs)
RhD- Blood
Attach PBMC
RhDPeptide
1 Hour(remove)
2
Days
IL-4GM-CSFIL-1IL-6TNF-αPGE-2
CD83CD86HLA-DR
CD80
MatureDC-Like
Flow Cytometer Analysis
2-4 Days
CFSE-Labeled Fresh Autologous RhD- PBMC
CFSE
Proliferation
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 29
Is PEGylated RhD Immunogenic?
RhD Allorecognition: RhD- PBMC Proliferation Following RhD Peptide Presentation By RhD- APC at 48 Hours.
RhD Peptide(Pos. Control)
Proliferation
75%75%
No RhD(Neg. Control)
Proliferation
1.3%1.3%
SVA-mPEG RhD Peptide
Proliferation
0.5%0.5%
A B C
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 30
Reducing The “Flavors” of Blood? Reducing The “Flavors” of Blood?
Immunocamouflage of RhD Improving blood utilization and availability.
8 Crucial Flavors8 Crucial FlavorsSome Realatively Rare...
Immunocamouflaged RBCImmunocamouflaged RBC Type O ~ 44% Type A ~ 42%
Type B ~ 10% Type AB ~ 4%
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 31
Stealth RBC: Stealth RBC: The ChallengesThe ChallengesTo Being Famous and Rich
CorporateCorporateConsiderationsConsiderations
It is It is NOTNOT the next Viagra the next Viagra
Drug ApprovalDrug ApprovalProcess Process
$$$$
$$$$
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009
Transfusion-Associated Graft Versus Host Disease
32
Immunocamouflage of BloodImmunocamouflage of Blood
What About Other Blood Cells?
BLOOD
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 33
Paris HiltonParis Hilton®® School of Medicine: School of Medicine:
IMMUNOLOGY 101IMMUNOLOGY 101Paris HiltonParis Hilton®® School of Medicine: School of Medicine:
IMMUNOLOGY 101IMMUNOLOGY 101Multiple determinants on cells govern whether individuals may be Multiple determinants on cells govern whether individuals may be
potential tissues donors or tissue recipients.potential tissues donors or tissue recipients.
AntigensParis and Not Paris
AntigensParis and Not Paris
PARISPARIS
USUS
Stop
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 34
Immunocamouflage:Immunocamouflage:
Loss of AllorecognitionLoss of AllorecognitionImmunocamouflage:Immunocamouflage:
Loss of AllorecognitionLoss of Allorecognition
0
100 101 102 103 104
1000
FSC
-Hei
ght
CD28-FITC
72.88%
27.12%
Control
0
100 101 102 103 104
FSC
-Hei
ght
CD28-FI TC
0.20%
99.80%
10002.4 mM mPEG
per 1 x 107 cells
CD28+CD28+
T Cell APC
CD28 CD80 (B7)
Essential CostimulatoryPathway
3 H-T
hym
idin
e In
corp
orat
ion
(C
PM
)
0
10000
20000
30000
40000
2 .01 .00 0 .5 1 .5 2 . 5
Responder Cell Concentration (x 10Responder Cell Concentration (x 1055))
Unmodified
mPEG-Modified
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 35
Global Immunocamouflage of Either the APC or Lymphocyte Prevents Allorecognition
Both In Vitro and In Vivo
CONTROL mPEG-MODIFIED
Allorecognition
Costimulation
AdhesionXXXXXX
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 36
Reduce Risk of RBC Alloimmunization
Improved RBC Rheological Dynamics (Sickle Cell Anemia)
Improved Utilization of RBC (e.g., just say “NO!”toRhD)
Prevention of Transfusion Associated-GVHD
Cold Storage of Platelets
Potential Applications Potential Applications Include:Include:
A Need To Innovate:A Need To Innovate: ImmunocamouflageImmunocamouflage of Blood Cells is of Blood Cells is Easily and Effectively Accomplished.Easily and Effectively Accomplished.
A Need To Innovate:A Need To Innovate: ImmunocamouflageImmunocamouflage of Blood Cells is of Blood Cells is Easily and Effectively Accomplished.Easily and Effectively Accomplished.
This is not a broken MenorahThis is not a broken Menorah
BLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CABLOOD.CA WWW.BLOOD.CA WWW.BLOOD.CACanadian Blood Servicesit’s in you to giveMark D. Scott 04/2009 37
STUDENTS &POSTDOCSSTUDENTS &POSTDOCSAmanda Bradley, Ph.D.Amanda Bradley, Ph.D.Audrey Chen, Ph.D.Audrey Chen, Ph.D.YevgeniyaLeYevgeniyaLe, Ph.D., Ph.D.Kari Murad, Ph.D.Kari Murad, Ph.D.Troy SuttonTroy Sutton, Ph.D., Ph.D.Dan Wang, Ph.D.Dan Wang, Ph.D.
TECHNICIANSTECHNICIANSNobu Nakane, M.S.Nobu Nakane, M.S.Janet TongJanet TongWendy ToyofukuWendy Toyofuku
COLLABORATORSCOLLABORATORSJohn W. Eaton, Ph.D.John W. Eaton, Ph.D.Elisabeth Maurer, Ph.D.Elisabeth Maurer, Ph.D.Marshal Henri PétainMarshal Henri Pétain
STUDENTS &POSTDOCSSTUDENTS &POSTDOCSAmanda Bradley, Ph.D.Amanda Bradley, Ph.D.Audrey Chen, Ph.D.Audrey Chen, Ph.D.YevgeniyaLeYevgeniyaLe, Ph.D., Ph.D.Kari Murad, Ph.D.Kari Murad, Ph.D.Troy SuttonTroy Sutton, Ph.D., Ph.D.Dan Wang, Ph.D.Dan Wang, Ph.D.
TECHNICIANSTECHNICIANSNobu Nakane, M.S.Nobu Nakane, M.S.Janet TongJanet TongWendy ToyofukuWendy Toyofuku
COLLABORATORSCOLLABORATORSJohn W. Eaton, Ph.D.John W. Eaton, Ph.D.Elisabeth Maurer, Ph.D.Elisabeth Maurer, Ph.D.Marshal Henri PétainMarshal Henri Pétain
Immunocamouflage AcknowledgmentsImmunocamouflage AcknowledgmentsImmunocamouflage AcknowledgmentsImmunocamouflage Acknowledgments