dr. ladan shariat
TRANSCRIPT
www.worldcancercongress.org
Disclosure of Interest: None Declared Abstract code:
Early and accurate diagnosis of cancer, moving towards a solution.
Progress in cancer diagnosis through targeted imaging Dr. Ladan Shariat
SAT.1.395-4
Contact Information Dr. Mahmood Moshiri
Proteus Imaging Canada Inc.
330 Highway #7 East, Richmond Hill, ON, Canada
Tel: 905-881-1049 Cell: 416-450-6414 Fax: 905-881-2241
Confidential
HAAH Gene Expression in Leukemia Correlates with Gleevec Response
0%
20%
40%
60%
80%
100%
120%
0%
20%
40%
60%
80%
100%
120%
0%
20%
40%
60%
80%
100%
120%
HA
AH
/ б 2
M(R
elat
ive
to U
ntre
ated
)
Untreated Treated with Gleevec, 1йM in vitroCell Lines Patients
Untreated(¯ = 100.0 ; n = 41)x
Responders(¯ = 42.3 ; n = 28)x
Non-Responders(¯ = 96.1 ; n = 13)x
Non-Responders
(¯ = 97.2 ; n = 6)x
Responders
(¯ = 13.8 ; n = 6)x
New Subsidiary
Specificity = 93% Sensitivity = 95% *Men > 50 years of age, cancer-free
-10
10
30
50
70
90
110
130
HA
AH
(ng/
ml)
Non-Cancer*n = 43x =0
PSA <2n = 100x = 23.0
PSA 2-4n = 49
x = 21.1
PSA >4n = 84
x = 31.60Prostate Cancer
n = 233, x = 25.7
-10
10
30
50
70
90
110
130
HA
AH
(ng/
ml)
Non-Cancer*n = 43x =0
PSA <2n = 100x = 23.0
PSA 2-4n = 49
x = 21.1
PSA 2-4n = 49
x = 21.1
PSA >4n = 84
x = 31.60
PSA >4n = 84
x = 31.60Prostate Cancer
n = 233, x = 25.7 In House Imaging
Toxin-Antibody Drug (Cytotoxic Agents)
In House
Tissue Test
Joint Venture
FB50 - NL
Normal
FB50 - HCC
Liver Cancer
FB50 - NL
Normal
FB50 - NL FB50 - NL
Normal
FB50 - HCC
Liver Cancer
FB50 - HCC FB50 - HCC
Liver Cancer
HAAH-Based
Cancer Management (Personalized)
HAAH-Based Integrated Cancer Management
In House CLIA and FDA (USA)
Cancer Testing Laboratory (International)
Diagnostics (Companion)
Therapeutics (Immunotherapy)
Naked-Antibody Drug (Cytostatic Agents)
In House
Tum
or V
olum
e (m
m3 )
(Geo
met
ric M
ean,
n=1
2)
Day of Treatment
Gene Expression
% B
lank
140
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100
80
60
40
20Control 10 100 500 10 100 500
Antibody nM
All-Human Anti-HAAH
Chimerized Anti-HAAH
% B
lank
140
120
100
80
60
40
20Control 10 100 500 10 100 500
Antibody nM
All-Human Anti-HAAHAll-Human Anti-HAAH
Chimerized Anti-HAAHChimerized Anti-HAAH
Cel
lSur
viva
l
Toxin Antibody nM
Prostate Cancer
Serum Tests
TUMOR
KIDNEY
TUMORTUMOR
KIDNEY
TUMOR
Vaccine Therapy Protein on Nano-Particle Adjuvant
New Subsidiary
The Cancer Diagnostic/Imaging Platform
Proteus’ cancer detection and monitoring platform comprises two
key components:
A- The Target B-The Antibody
The Target: HAAH
Expressed by virtually all tumor cells Expressed exclusively by tumor cells Not expressed in normal adjacent tissue Expressed on the cell surface Expressed at the margins of tumors Expressed across multiple types of cancer
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Expressed by virtually all tumor cells
HAAH has been detected in all cancer types tested (n>20) including: liver, bile duct, brain, breast, prostate, colon, ovary, pancreas and in nearly 100% of all cancer specimens (n>1,000)
Leukemia Lung Carcinoma
Breast Cancer Pancrea3c Cancer
Cancerous and Normal Bile Duct
Cholangiocarcinoma Cholangiocarcinoma
Prolifera3ng Sclerosing Cholangi3s (PSC)
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Expressed exclusively by tumor cells
Normal Prostate Benign Prosta3c Hyperplasia Prostate Cancer
HAAH was not detected in over 500 non-cancerous tissues including proliferative disorders
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Not expressed in normal adjacent tissue
BREAST CANCER TISSUE SHOWS POSITIVE IMMUNOHISTOCHEMICAL STAINING FOR HAAH
B
A
Note dis3nct staining of involved ducts (A). Adjacent uninvolved 3ssue does not stain (B).
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HAAH - Expressed on the cell surface
Normal Liver Control Liver Cancer Dual Stain HAAH &
Membrane
• Surface localiza3on is confirmed by dual staining with a membrane specific dye (Di-‐I).
The Target: HAAH
Expressed by virtually all tumor cells Expressed exclusively by tumor cells Not expressed in normal adjacent tissue Expressed on the cell surface Expressed at the margins of tumors Expressed across multiple types of cancer
The Antibody
-All-human sequence antibody -Enhanced binding for greater sensitivity and specificity -Improved target reach and clearance, for faster procedures -Reduced risk of allergic response during follow-up tests -Efficiency in product manufacturing
HAAH-Based Imaging
Can visualize tumors in various organs Location and size Monitoring over time Treatment monitoring All-human antibody allows for repeat imaging Antibody binding is rapid and strong It clears rapidly from the kidney.
Visualization Modality
Can use any standard contrast/ chromophor Quick way is the use of radioactive label and currently available cameras No new equipment and supplies needed
Application in Animals
TUMOR
KIDNEY
TUMOR
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Top Ten Medical Breakthroughs-Time Magazine
Panacea Laboratories - MD - USA
Panacea at UICC-ASCO-Roundtable Meeting
19
On 4Panacea at UICC-ASCO-Roundtable Meetinge University of Texas MD Anderson Cancer Center (MDACC) and the Union for International Cancer
Control (UICC)-ASCO-ACS-WHO-…..-PANG
20
UICC Global Partners
www.worldcancercongress.org
Disclosure of Interest: None Declared Abstract code:
Nanoparticle Based Vaccine Development “Therapeutic Cancer Vaccine”
Progress in cancer vaccine therapy Dr. Mahmood Moshiri
SAT.1.395-4
Nanoparticle Based Vaccine Development
Therapeutic Cancer Vaccine
Contact Information Dr. Mahmood Moshiri
Panacea Pharmaceutical Inc. 209 Perry Parkway, Suite #13,
Gaithersburg, MD, USA Tel: 905-881-1049 Cell: 416-450-6414 Fax: 905-881-2241
Safe Harbour Statement
Statements in this presentaCon that are not strictly historical are “forward-‐looking” and involve a some degree of risk and uncertainty. These include, but are not limited to, statements related to Panacea’s technology and product candidates (including Panacea’s ability to idenCfy, develop and commercialize new products and product candidates, either independently or with collaboraCon partners, and Panacea’s Cmetable for doing so), lines of business, markets (including market size and Panacea’s ability to idenCfy, develop and commercialize products to address those markets), operaCons (including Panacea’s ability to successfully negoCate and enter into collaboraCon partnerships), capabiliCes, commercializaCon acCviCes, customer adopCon rates, industry condiCons, future financial performance, and near-‐term and longer-‐term growth and prospects. Such statements are only predicCons, and actual events or results may differ materially from those projected in such forward-‐looking statements. Factors that could cause or contribute to the differences include, but are not limited to, risks associated with Panacea’s strategic focus, technologies and products (including Panacea’s ability to idenCfy, develop and commercialize new products, either independently or with collaboraCon partners, and market demand for these product and product candidates), dependence on patents and proprietary rights, protecCon and enforcement of its patents and proprietary rights, the commercial prospects of the industries in which Panacea operates and sells products, Panacea’s dependence on manufacturing and/or license agreements, its ability to achieve milestones under exisCng and future collaboraCon agreements, the ability of Panacea’s and its partners to commercialize its products (including by obtaining any required regulatory approvals) using Panacea’s technologies, the Cming for launching any commercial products and projects, the ability of Panacea’s and its collaborators to market and sell any products that it or they commercialize, the development or availability of compeCCve products or technologies, the future ability of Panacea’ to enter into and/or maintain collaboraCon and joint venture agreements and licenses on a Cmely basis or at all. These forward-‐looking statements speak only as of the date hereof, and Panacea expressly disclaims any intent or obligaCon to update these forward-‐looking statements.
PRIVATE & CONFIDENTIAL
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HAAH is a Cancer Biomarker
• Panacea discovered that HAAH is elevated in the sera of individuals with cancer • Panacea has developed a specific and sensitive immunoassay to detect HAAH in serum • Panacea has also developed a sensitive qRT-PCR methods for detecting HAAH gene expression
HAAH is an excellent target for a therapeutic cancer vaccine
• It is expressed on cancer cells and not on non-cancer cells
• Its function is consistent with the etiology of cancer: growth, motility and invasiveness of cancer cells
• Monoclonal antibodies to HAAH have proven to have efficacy in both in vitro and in vivo
Rationale for Design of Nanoparticle Vaccine
Using Bacteriophage for recombinant vaccine production and nano-particle based vaccine.
• Inexpensive • Robust • Quick • Effective
Concept
Surface Repertoire of Lambda Phage
Surface Expression of Protein In vitro expression of antigen on lambda phage prior to inoculation in animals
Designing lambda phage system to display antigenic proteins
as a C terminus fusion product of gpD
Phage Presentation of Antigen
Gives the vaccine the ability to target professional immune cells.
gpD-chimeric recombinant lambda phage particles specifically bind with dendritic or other antigen presenting cells.
The Phage Cloning Process
The Phage Cloning Process!
• Protein sequences of HAAH and AAH of rat, mouse and chicken. Note the high degree of homology among the sequences, particularly the C-terminal portion of the molecule.!
• Three different portions of the HAAH molecule were cloned into the lambda phage as fusion proteins with lambda gpD (see sequences at right). The resulting protein sequences are of the following sizes:!
• HAAH-1λ (N-terminal portion of HAAH): Total length of ORF = 324 aa, Cloned HAAH antigen = 199 aa!
• HAAH-2λ (mid portion of HAAH): Total length of ORF = 302 aa, Cloned HAAH antigen = 176 aa!
• HAAH-3λ (C-terminal portion of HAAH): Total length of ORF = 349 aa, Cloned HAAH antigen = 225 aa!
Protein Sequence of HAAH and Species Homology
Manufacturing Process for Nanoparticle Vaccine Growth and Purification
Process Data for Nanoparticle Vaccines
Growth and purification data for HAAH lambda phage constructs Note that nanoparticles are determined using a particle analyser
Plaque Immunoblot with FB50 monoclonal antibody!(specific for N-terminal portion of HAAH)!
Analysis of HAAH Phage Constructs
Western Blot of rHAAH and phage constructs with FB50 monoclonal antibody (specific for N-terminal portion of HAAH)!
Analysis of HAAH Phage Constructs
HAAH antigen ELISA using FB50 capture and conjugate to detect N-terminal portion of HAAH. Green bars are the HAAH standard curve, brown bars the HAAH-1λ construct and red bars the parental phage.
Analysis of HAAH Phage Constructs
Immunogenicity Results – Dose Response Study Day 22
Vaccine Doses given Days 1, 8, 15
Immunogenicity Results – Number of Doses
ELISA testing of mouse sera on plates coated with recombinant HAAH (left panel) or the HAAH-1λ vaccine. (right panel). Mice were immunized with 1x1010 pfu of HAAH-1λ vaccine on Days 1 (1 dose), 1 and 8 (2 doses) or 1, 8 and 15 (3 doses). Sera were obtained on Days 21 and 36.
Immunogenicity Results – Binding to Cancer Cells
ELISA testing of mouse sera on plates coated with human lung cancer cell line H460 (left panel) and the human liver cancer cell line FOCUS (right panel) (5x104 cells seeded in the microplate wells and grown for 48 hours). Mice were immunized with 1x1010 pfu of HAAH-1λ, HAAH-2λ or HAAH-3λ vaccine on Days 0, 7, 14 and 58. Sera were obtained on Day 93.
Immunogenicity Conclusions
All three constructs (HAAH-1λ, HAAH-2λ or HAAH-3λ) demonstrated production of antibody against the nanoparticle vaccines Antibody levels demonstrated a clear dose-response to the vaccines Antibody levels demonstrated a clear response to the number of doses The observation that the mouse sera show a higher upper limit of binding to the antigens than does FB50, is consistent with a polyclonal response to the vaccine. Antibodies generated to the nanoparticle vaccines bind to cancer cells in ELISA , and by cell sorter analysis demonstrating the potential for efficacy against tumors
Tumor Challenge Studies
Tumor challenge mouse model • Mouse hepatocellular carcinoma cell lines BNL and BNLT3
injected subcutaneously in the flank • Mice receive 3 x weekly doses of nanoparticle vaccine (each
group of mice receives one HAAH construct) or placebo • Mice are evaluated twice-weekly for tumor growth • Sera obtained for determination of antibody titers at one or more
intermediate time points and at end of study Challenge studies with other tumor cell types continue in progress
Tumor Challenge Results – Prophylaxis with HAAH-1λ
Using the hepatocellular carcinoma cell line BNLT3. Mice were immunized subcutaneously on Days 0, 7, 14, 46 and 62 with 1 x 1010 pfu of the HAAH-1λ phage construct or phage control and challenged subcutaneously on Day 46 with 5 x 104 BNLT3 cells. Tumor volume (mm3) = length x width2 x 0.5.
Tumor Challenge Results – Prophylaxis, All Constructs
Tumor challenge study in mice using the hepatocellular carcinoma cell line BNLT3. Groups of 10 mice were immunized subcutaneously on Days 0, 7, 14 and 57 with 1 x 1010 pfu of the HAAH-1λ, HAAH-2λ or HAAH-3λ phage construct or buffer control and challenged subcutaneously on Day 50 with 5 x 103 BNLT3 cells. Left panel shows growth for individual groups and right panel shows pooled data for the HAAH constructs. *p<0.05, **p,0.01
Tumor Challenge Results – Treatment, HAAH-1λ Vaccine
Study of effect of vaccination on established tumors in mice. Mice were immunized on Days 0, 7 and 14 with 1 x 1010 pfu of HAAH-1λ vaccine and with 5 x 104 BNLT3 cells subcutaneously on Day 22. By Day 42, tumors were present in all animals. On Day 42, mice were boosted with 1 x 1010 pfu HAAH-1λ and observed for further effect on tumor size. Data are presented with Day 47 tumor volume subtracted. *p<0.05,**p<0.01 .
Tumor Challenge Results – Treatment, All Constructs
Treatment tumor challenge study in mice. Groups of 5 mice were challenged subcutaneously on Day 0 with 5 x 103 BNLT3 cells and immunized on Days 0, 7 and 14 with HAAH-1λ, HAAH-2λ, HAAH-3λ phage vaccine or buffer control. Upper panel shows growth for individual groups and lower panel shows pooled data for the HAAH constructs. *p<0.05 .
Tumor Challenge Study Conclusions – BNLT3 Liver Cancer Models
• Vaccination with the HAAH phage constructs inhibits BNLT3 liver cancer cell growth prophylactically. Fewer animals had tumours and growth was less in the vaccine groups compared to the control groups.
• The HAAH-1λ vaccine can slow the growth of established tumors. The difference was highly significant compared to the non-treated group.
• Giving Nanoparticle vaccine and BNLT3 liver cancer cells (together)can inhibit tumor growth. Also, fewer animals had tumor growth in the treated groups.
• The nanoparticle therapeutic cancer vaccine targeting HAAH is effective in inhibition of tumor growth in mice under various conditions
Breast Cancer Cell Tumor Challenge Results – Enhanced Survival with Nanoparticle Vaccine
Summary of Nanoparticle Vaccine for Cancer Vaccine target is common to all cancer types Intellectual property is securely held by Panacea Simple manufacturing process with high yields
• For example, a 2 liter culture yields 2,000 – 5,000 doses Vaccine is safe
• Contains non-replicating bacterial virus • Minimal anticipated side effects
Easy to administer • Small number of doses and dose volumes • Long-lasting effect
Regulatory environment is favorable • No long-term toxicology studies required • May qualify as Breakthrough Therapy or Fast Track Product
Overall Conclusions
• Panacea Pharmaceuticals has developed a robust vaccine therapeutic drug candidate based on the cancer-specific antigen HAAH that is demonstrated to be immunogenic and efficacious in animal models of cancer. • Panacea is proceeding to prepare an Investigational New Drug Application (IND) submission to FDA for the purpose of Phase 1 clinical testing in human subjects
Panacea Laboratories - MD - USA
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