Transcript Functionalized Carbon Nanotubes in Cancer Therapy

Antibody-Functionalized Carbon
Nanotubes in Cancer Therapy
Kyung Kim , Kristina Tran, and Dr. Miguel Bagajewicz
April 28, 2008
Project Overview
Project Overview
Project Overview
NIR laser
Mathematical
models
PATIENT
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Outline
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Breast cancer in the US
Antibodies and SWNTs
Cancer therapy using mAb with SWNTs
Tumor angiogenesis
Mathematical models
Photothermal therapy
Large-scale production
Economics
Future studies
Introduction
mAb
SWNT
Estimated Cancer Deaths for
Women (2008)
Lung
71,030
Breast
40,480
Angiogenesis
Colon
25,700
PBPK Model
Pancreas
16,790
Ovary
15,520
Conjugated
Therapy
Photothermal
Therapy
Large-scale
Production
Uterine
7,470
Economics
Conclusion
Source: Cancer Facts & Figures 2008, American Cancer Society,
<http://www.cancer.org/downloads/STT/2008CAFFfinalsecured.pdf>
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Treatment Options
• Surgery
– Not convenient
– Mastectomy
• Radiation Therapy
– Can also damage normal surrounding cells
• Chemotherapy
– Normal cells subject to random attack
Economics
Conclusion
Source: Seattle Cancer Care Alliance <http://www.seattlecca.org>
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
IGF1R, HER2 Receptor
• Insulin-like growth factor 1 receptor
(IGF1R) is highly expressed in human MCF7
ER+ breast cancer, lower expressed in
BT474 ER• Human endothelial receptor 2 (HER2) is
highly expressed in human BT474 ER- breast
cancer, lower expressed in MCF7 ER+
Large-scale
Production
Economics
Conclusion
Source: Xiang R, Shi Y, Dillon D A, Negin B, Horv´ath C and Wilkins J A 2004 J. Proteome Res. 3 1278
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Monoclonal antibodies
• Antibodies – globular proteins synthesized
by B lymphocytes in animals
– Are produced in response to a foreign
substance.
• Monoclonal antibodies – are identical
because they are produced by one type of
immune cell
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Introduction to Carbon
Nanotubes
• Carbon nanotubes (CNT)
– Hollow cylindrical structures
made from carbon
– Single-walled carbon
nanotubes (SWNT)
– Multi-walled carbon
nanotubes (MWNT)
Large-scale
Production
Economics
Conclusion
Source: Li et. al, Cardiovascular Effects of Pulmonary Exposure to Single-Wall Carbon Nanotubes,
Environmental Health Perspectives 115:3 (2007).
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Properties of CNTs
• Can conduct electricity and heat
• Tougher and stronger than steel
• Strong in high acidic and high temperature
environments
• Strong absorbance in the near-infrared
regime
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Source: Nano Science and Technology Institute, <http://www.nsti.org/news/item.html?id=50>
Applied Nanotechnologies Inc, <http://www.applied-nanotech.com/cntproperties.htm>
mAb
Nanostructure-mediated Drug
Delivery
SWNT
• Nanostructured drug carriers
Introduction
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
– Can penetrate barriers that are difficult in
conventional drug delivery
– Can deliver the drug treatment directly into the
cells
– Can penetrate tumors due to the “leaky” nature
of the tumor vasculature
Large-scale
Production
Economics
Conclusion
Source: Hughes, G., Nanostructure-mediated drug delivery, Nanomedicine: Nanotechnology, Biology, and
Medicine I (2005), 22-30.
Introduction
mAb
SWNT
mAb-SWNT Conjugation
• SWNTs have a hydrophobic, π-electron-rich
surface
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Source: Erlanger, B., Chen, B., Zhu, M., Brus, L., Binding of an Anti-fullerene IgG monoclonal antibody to
single wall carbon nanotubes, Nano Letters (2001), 1(9):465-467.
Source: Panchapakesan, B. et. al. Nanotechnology 18 (2007) 315101
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Routes of Internalization
• Passive diffusion across lipid bilayer similar
to a nanoneedle
• Uptake by endocytosis
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Cancer Cell Killer
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Cancer Cell Killer
Introduction
Steps Involved in Tumor Angiogenesis
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Source: Kuszyk, B. S. et al. Am. J. Roentgenol. 2001;177:747-753
Copyright © 2007 by the American Roentgen Ray Society
Introduction
Steps Involved in Tumor Angiogenesis
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Growth of the interstitium is induced by
tumor cells in a process similar to
healing. Host capillaries dilate and
develop increased permeability.
Source: Kuszyk, B. S. et al. Am. J. Roentgenol. 2001;177:747-753
Copyright © 2006 by the American Roentgen Ray Society
Introduction
Steps Involved in Tumor Angiogenesis
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Fibrin leaks from blood pool into interstitium,
creating extracellular matrix that facilitates cell
growth. Proteases and collagenases break
down capillary basement membranes.
Source: Kuszyk, B. S. et al. Am. J. Roentgenol. 2001;177:747-753
Copyright © 2007 by the American Roentgen Ray Society
Introduction
Steps Involved in Tumor Angiogenesis
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Source: Kuszyk, B. S. et al. Am. J. Roentgenol. 2001;177:747-753
Copyright © 2007 by the American Roentgen Ray Society
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Tumor Angiogenesis
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Molecular Transport
• Diffusion
– Driven by concentration gradients
• Convection
– Driven by pressure gradients
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Intravenous Injection
• Direct infusion of drugs to tumors directly
can overcome biological barriers
• However, the residue time of drugs using
direct injection inside of tumor cells is
short compared to the intravenous
injection
• Imaging-guided, minimally invasive
approaches are desired
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Mathematical Model
• Determine the initial dose of drugs to reach
into the tumor volume based on the size of
tumor cells
– Physiologically based model
– Two-pore model
– Subcompartments model
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Physiologically Based
Pharmacokinetic Model (PBPK)
Structure of the
mathematical
models based on
the physiological
connectivity
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Source: Davda, J. P., Jain, M., Batra, S. K., Gwilt, P. R., Robinson, D. H., A physiologically based pharmacokinetic (PBPK)
model to characterize and perdict the disposition of monoclonal antibody CC49 and its single chain Fv constructs, International
Immunopharmacology (2008) 8, 401-413.
Source: G. Z. Ferl, A. M. Wu, J. J. Distefano III, A predictive model of therapeutic monoclonal antibody dynamics and regulation
by the newnatal Fc Receptor (FcRn), Annals of Biomedical Engineering, Vol. 33, No. 11, Nov. 2005, pp. 1640-1652
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Characteristics of our PBPK
Model
1) Blood circulation through bloodstream
2) Transportation of mAb through the
capillary wall
3) Lymph flow for circulation of mAb
4) Binding specificity
5) FcRn receptor in liver, skin and muscle
6) Catabolic clearance
7) Elimination of catabolic products
Introduction
Lung
CLLU
mAb
QB
Blood
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
QT
Tumor
CLT
QH
Heart
CLH
Liver
CLLi
QLi
Spleen
CLSP
QSp
QB
CLRB
Rest of Body
QK
Kidney
U
Source: Davda, J. P., Jain, M., Batra, S. K., Gwilt, P. R., Robinson, D. H., A physiologically based pharmacokinetic (PBPK)
model to characterize and perdict the disposition of monoclonal antibody CC49 and its single chain Fv constructs, International
Immunopharmacology (2008) 8, 401-413.
Introduction
mAb
SWNT
Conjugated
Therapy
Two-pore Model
• The two-pore theory of macromolecule
extravasation
• Diffusion and convection occurred in the
Large (~50 nm) and small pores (~10 nm)
Angiogenesis
PBPK Model
Photothermal
Therapy
Jv : Fluid flux
αL, αS : Fraction of bulk
fluid (large and small pore)
Large-scale
Production
Economics
Conclusion
Source: Davda, J. P., Jain, M., Batra, S. K., Gwilt, P. R., Robinson, D. H., A physiologically based pharmacokinetic (PBPK)
model to characterize and perdict the disposition of monoclonal antibody CC49 and its single chain Fv constructs, International
Immunopharmacology (2008) 8, 401-413.
Introduction
mAb
SWNT
Conjugated
Therapy
Subcompartments Model
QORG
Q ORG- LORG
Vascular space
JORG
LORG
Interstitial space
Angiogenesis
krec
kint
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
kint : Rate constant of internalization
kcat: Rate constant for lysosomal
degradation
krec: Rate constant for recycling of FcRn bound
Cm: Conc. of catabolites
CLorg: Catabolite clearance rate
Endosome
kcat
Cm
CLORG
Introduction
mAb
Equations for Two-pore
Model
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
R: Partition coefficient
Pe: Peclet number
σ: Osmotic reflection
coefficient
Economics
Conclusion
Source: Rippe B, Haraldsson B., Transport of macromolecules across microvascular walls: the two-pore
theory., Physiol Rev (1994) 74(1), 163-219.
Parameters for Simulation
There are 26 ODEs
with 138
parameters used to
describe this
mathematical model
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Introduction
Ratio of mAb concentrations in the body
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Begin NIR treatment here
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Photothermal Therapy
• Near-infrared region: 700-900 nm
– For breast cancer tumors in literature, 800 nm
laser was used over a range of 0.8-3.5 W/cm2 for
up to 3 min.
• Temperature range of heated target tissue:
55-90ºC
• The energy used in the destruction of
cancer cells: 200 nW/cell
Large-scale
Production
Economics
Conclusion
Source: Kam, N. et al., Carbon nanotubes as multfunctional biological transporters and near-infrared
agents for selective cancer cell destruction, Proceedings of the National Academy of Sciences (2005).
Source: Whelan, W.M. et al., A novel strategy for monitoring laser thermal therapy based on changes in
optothermal properties of heated tissues, International Journal of Thermophysics (2005).
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Mathematical Thermal Modeling
• For medical laser treatment, it is helpful to
know temperature distribution
• Not practical to implant temperature
probes in the body
• Used to optimize treatment parameters for
laser therapy
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Source: Jiang, S.C. and Zhang, X.X., Dynamic modeling of photothermal interactions for laser-induced
interstitial thermotherapy: parameter sensitivity analysis, Lasers in Medical Science (2005), 20:122-131.
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Number of Cancer Cells in a
Colony
• The exact number of cancer cells in a
colony of tumor cells is very difficult to
determine
• 200 nW/cell required for killing one cancer
cells in a colony
• F. L. Meyskens, Jr., et al. found the
relationship between the diameter of cells
and the diameter of a colony
Calculating the Number of
Cancer Cells
• F. L. Meyskens, Jr., et al. developed the
equation for the number of cells in a tumor
colony
ln ( no . of cells / colony )  0 . 874
 2 . 804 ln( D cell )  2 . 378 ln( D tumor )
• Hypoxia – tumor cells cannot move too far
away form the blood vessels
• Critical distance – 100 µm
Source: Meyskens, F., Thomson, S., Moon, T., Quantitation of the Number of Cells within Tumor
Colonies in Semisolid Medium and Their Growth as Oblate Spheroids, CANCER RESEARCH 1984,
271-277.
Introduction
mAb
Number of Cells in Tumor
Colonies
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Source: Meyskens, F., Thomson, S., Moon, T., Quantitation of the Number of Cells within Tumor
Colonies in Semisolid Medium and Their Growth as Oblate Spheroids, CANCER RESEARCH 1984,
271-277.
Introduction
mAb
Distribution of Diameter of Cells
Inside of Tumor Colony
180
SWNT
160
Conjugated
Therapy
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Frequency
Angiogenesis
140
120
100
80
60
40
20
0
0.00005
0.0001
0.00015
0.0002
Diameter (m)
More
Introduction
mAb
Calculating the Number of
Cancer Cells
Mean Colony Diameter (Tumor Diameter in m)
0.0267301
0.030598
0.033678
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
D (m)
Number of Cells in a Colony
3.852E-05
1.039E+09
1.43E+09
0.0001967
10742693
14814767
7.182E-05
181176759
2.5E+08
0.0001596
19308632
26627671
8.554E-05
110972827
1.53E+08
0.0001391
28359665
39109546
0.0001413
27140521
37428278
0.0001985
10466141
14433387
0.0001721
15634122
21560319
4.163E-05
835869154
1.15E+09
0.0001009
69827941
96296589
9.9E-05
73667014
1.02E+08
4.261E-05
783377904
1.08E+09
4.622E-05
623317707
8.6E+08
0.0001627
18290277
25223303
6.426E-05
247438303
3.41E+08
8.261E-05
122358835
1.69E+08
9.546E-05
81579267
1.13E+08
0.0001474
24113506
33253858
1.8E+09
18609281
3.14E+08
33447831
1.92E+08
49126695
47014803
18130218
27082575
1.45E+09
1.21E+08
1.28E+08
1.36E+09
1.08E+09
31683761
4.29E+08
2.12E+08
1.41E+08
41771186
0.036278
2.15E+09
22209917
3.75E+08
39919519
2.29E+08
58632023
56111510
21638162
32322674
1.73E+09
1.44E+08
1.52E+08
1.62E+09
1.29E+09
37814126
5.12E+08
2.53E+08
1.69E+08
49853326
Calculating the Number of
Cancer Cells
TD = 0.0337
TD = 0.03627
TD = tumor diameter
Histogram
1400
1200
1000
800
600
400
Bin
More
80516541685
76044578519
71572615353
67100652187
62628689021
58156725855
53684762689
49212799523
44740836357
40268873191
35796910025
31324946859
26852983693
22381020527
17909057361
13437094195
8965131029
0
4493167863
200
21204696.67
Bin
Frequency
21204697
1
2.26E+09
1306
4.49E+09
76
6.73E+09
33
8.97E+09
16
1.12E+10
16
1.34E+10
3
1.57E+10
6
1.79E+10
7
2.01E+10
4
2.24E+10
4
2.46E+10
5
2.69E+10
4
2.91E+10
1
3.13E+10
2
3.36E+10
5
3.58E+10
3
Frequency
Bin
Frequency
17767026
1
1.89E+09
1305
3.76E+09
76
5.64E+09
33
7.51E+09
16
9.39E+09
16
1.13E+10
3
1.31E+10
6
1.5E+10
7
1.69E+10
4
1.88E+10
4
2.06E+10
5
2.25E+10
4
2.44E+10
1
2.62E+10
2
2.81E+10
5
3E+10
3
Wavelength
808nm
Energy
Assumed that 100% energy is absorbed by SWCNT
0.8W*cm^-2
time
Tumor Volume (ml)
3min
180sec
Tumor Volume (L)
0.01
0.015
200nW/cell-->
0.02
0.025
0.026730092
150nm -->
25
0.030598317
0.033677806
0.036278317
200µm -->
0.0000002W/cell
1.2nm -->
0.0002m
Number of cells in a colonies
0.000015cm
Diameter of one SWCNT
(minimum)
2387324.146
3580986.22
4774648.293
5968310.366
(random)
1091776197
1505619715
1891254894
2257186280
1.2E-07cm
Surface Area (cm^2)
5.655E-12
Energy used in the destruction of tumor cells (W)
(minimum)
0.477464829
0.716197244
0.954929659
1.193662073
(random)
218.3552394
301.123943
378.2509787
451.4372559
(minimum)
1.05543E+11
1.58314E+11
2.11086E+11
2.63857E+11
(random)
4.82671E+13
6.6563E+13
8.36118E+13
9.97895E+13
Energy emitted by one SWCNT
Number of SWCNT required to destroy the tumor cells
4.524E-12W
Radius of C
Total amount of SWCNT (mol)
7.7E-09cm
1.54E-08cm
(minimum)
(random)
1.75233E-13
2.6285E-13
3.50466E-13
4.38083E-13
8.0138E-11
1.10515E-10
1.38821E-10
1.65681E-10
Number of Carbon in the length of SWCNT
TC value of Antibodies (%)
7.21
974.02597
Number of Carbon in the height of SWCNT
24.479943
Total number of Carbons in one SWCNT
4.94
3.75
3.02
Initial dose SWCNT required (mole)
(minimum)
2.43042E-12
5.32084E-12
9.34577E-12
1.45061E-11
(random)
1.11148E-09
2.23714E-09
3.70189E-09
5.48612E-09
23844.1
Initial dose antibody used (mole)
MW of 1 SWCNT
286129.2g/mol
20
Biggest diameter in one cell can have due to hypoxia
Length of one
SWCNT
Diameter
15
Diameter of Tumors(m)
The energy used in the destruction of cancer cells
0.077nm
Assumed that the tumor is a sphere
10
1.11E-09
286129201mg/mol
2.50E-09
4.00E-09
6.00E-09
Transient Heat Transfer
• Finite difference model (explicit method)
• Convection and constant heat generation
– Modeled radiation heat flux as a constant
volumetric heat generation
– Modeled ambient water as convective surface
boundary

Q
Surface
i

i
 E gen   Vc p
T
i 1
m
T
i
m
t
Source: Yunus A. Cengel, Heat and Mass Transfer: A Practical Approach 3rd Edition., Mc Graw Hill,
2007, 313.
Temperature Contours of a
Tumor Cell During Irradiation
After 1 min
After 2 min
After 3 min
Temperature Contours of a
Tumor Cell After Irradiation
After 1 min
After 5 min
After 3 min
After 10 min
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Temperature Profile of Tumor
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale Production of mAb
• Bioreactor section
• Recovery section
– Membrane filter to remove biomass and other
impurities
• Purification section
– Three chromatography columns
– Diafiltration
– Sterilization
Large-scale
Production
Economics
Conclusion
Source: Harrison, R., Todd, P., Rudge, S., and Petrides, D., Bioseparations Science and Engineering
(2003), pg 362-367.
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Large-scale Production of MAb
Attached to SWNT
• Preparation of SWNT in suspension (PBS)
– Bead mills to break up the bundle
– Centrifuge
• Addition of surfactants to SWNT
– PEG as the surfactant (forms a monolayer)
– Mix in methanol
– Filter SWNT solution
• Conjugation with Mab
– Mix SWNTs with Mab and let it incubate at
room temperature
– Centrifuge
Shao, N., Lu, S., Wickstrom, E., and Panchapakesan, B., Integrated molecular targeting of IGF1T and HER2
surface receptors and destruction of breast cancer cells using single wall carbon nanotubes, Nanotechnology (2007),
18:1-9.
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Large-scale Production of MAb
Attached to SWNT
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Expected Production Rates
• We need to produce
– 1,797 mg/yr/patient of the MAb-SWNT
conjugate
• Assumptions
– 25% breast cancer patients will take the
treatment
– Treatment is administered 52 times a
year (weekly)
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Preliminary Market Analysis
• The global market for monoclonal
antibodies is projected to be $16.7 billion in
2008.
• Monoclonal antibodies for cancer therapy
were projected to be $7.2 billion
– 43% of the market share
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Source: Reichert et al., Monoclonal Antibodies Market, Nature Reviews,Vol. 3 (2004).
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Costs
• Total product cost
– $470 million
– $760/gram
• Fixed capital investment
– $107 million
• Total capital investment
– $128 million
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Net Present Value
• Minimum selling price is $1340/g (or 1.75
times the product cost)
• NPV is $542 million
– Based on economic lifetime of 10 years
– Based on selling price of twice the product cost
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Conclusion
• We have successfully modeled
– the initial dosage requirement of the drug as a
function of tumor volume
– the required time for NIR emission following
injection
– the temperature gradient of the tumor cell
during NIR irradiation
– the required time for tumor damage
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Conclusion
• Based on the simulation of the
temperature gradient for a tumor, the
damage to the surrounding tissue will
be minimal due to the small amount of
energy emitted from the NIR laser.
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Future Studies
• Pharmacokinetics of functionalized carbon nanotubes not
widely researched
• Need to find a way to determine if a patient has
overexpression of HER2
• Need to know the exact location of the tumor so we can
minimize diffusion time and cross all the major barriers
• FDA profit and probability analysis
• Need to better analyze number of treatments/year
• Use of SWNTs as multifunctional systems by attaching
therapeutic and imaging molecules to target tumors
Introduction
mAb
SWNT
Conjugated
Therapy
Angiogenesis
PBPK Model
Photothermal
Therapy
Large-scale
Production
Economics
Conclusion
Acknowledgements
• We would like to thank the following
for their help in our project:
–
–
–
–
–
–
–
Dr. Miguel Bagajewicz
Chiranth Srinivasan
Dr. Daniel Resasco
Dr. Lance Lobban
Dr. Liang Zhang
Dr. Barbara Safiejko-Mroczka
Kevin Bagnall
Questions?
APPENDIX
Catabolism of Antibodies
• Proteolytic Degradation
• Neonatal Fc Receptor (Fc-Rn)
Schematic of Antibody
Degradation
Catabolism of SWCNTs
• Opsonization
Calculation of Number of Cancer
Cells
• Calculation
of the minimum number of
cancer cells in a colony based on Hypoxia
theory (Dcell = 200 µm)