Transcript Document

Antibodies as Immune Modulators:
Combinatorial Immunotherapy
of Cancer
Madi R. Madiyalakan, PhD
Chief Executive Officer
Quest PharmaTech Inc.
8123 Roper Road NW, Edmonton, Alberta,
Canada
Company Overview
• Quest PharmaTech is
– a publicly traded Canadian biotechnology
company
– developing a portfolio of product candidates for
the treatment of cancer
– by combining proprietary antibodies with
• chemotherapy
• immuno-stimulants
• photodynamic therapy
• Oregovomab for treatment of Ovarian Cancer
is in a 80 patients Phase II clinical trial
Quest’s Approach For Cancer Treatment
• Cancer immunotherapy
• Proprietary use of Anti-cancer Antibodies as
Immune Modulators
• Combinatorial Immunotherapy is superior to
Mono-immunotherapy
• Engineered anti-cancer IgE antibodies may be
comparable, complementary, or even superior
to their IgG counterparts
Cancer Immunotherapy
• Enlisting the body to fight cancer
• Stimulating your own immune system to
work harder and/or smarter
• Increase the specificity and amount of
anti-cancer immunologic factors
Renewed Optimism For Immunotherapy of
Cancer: Newest Approvals
• In 2010 two immunotherapy products were
approved for cancer treatment
– Provenge (Sipuleucel T) by Dendreon, an
autologus dendritic cell therapy for prostate
cancer
– Yervoy(Ipilimumab) by BMS, a checkpoint
blockade inhibiting antibody for melanoma
• Unifying lesson
– Tumor directed immunity can treat cancer
– Tumor specific T cells in a favorable immune
regulatory state can control advanced cancer
Antibodies as Immunemodulators
• Most Therapeutic Antibodies used as “drugs”
• Developed based on Receptor Targeting and
interference
• Pharmacological Dose response requiring high
administered doses based on molecular weight
(examples Herceptin, Avastin, Rituxan, etc)
• In contrast, Quest uses IgG to induce immunity to
target Self Antigens (lower immunologic dose)
Antibodies as Immunemodulators
 Low dose (about 2 mg),
intravenous administration
of a xenotypic antibody to
TAA
 After injection, antibody
binds to cancer antigen and
forms immune complexes
 The complexes are cross
processed and presented
by dendritic cells to
activate T-cells
CA125-B43.13 Complex
CA125 conjugated with
FITC (green)
pre-incubated with MAbB43.13-Cy3 (red)
added to day 5 DC for 30
min. before fixation;
yellow: co-localized
complex
Antibodies as Immunemodulators
Anti-MUC1 Ab Clinical Experience
• MUC1 is a dominant tumor antigen on most
adenocarcinoma
• Colon, lung, pancreas, ovary, pancreas,
multiple myeloma, others
• Mucinous glycoprotein differentially expressed
in malignant tissue
– hypoglycosylated in malignancy and expressed on
all cell surfaces
– a distinct immune target
MAb AR20.5 Clinical Studies: Phase I
Objectives:
• To determine the safety of MAb AR20.5 administered
intravenously on weeks 1, 3, 5, 9, 13, and 17 at 3 defined
dose levels
• To assess the humoral and cellular immune responses
induced by MAb AR20.5
• To assess preliminary anti-tumor responses
MAb AR20.5 Clinical Studies: Phase I
Immunological Response Results
Summary:
• HAMA, Ab2, anti-MUC1 antibodies and T-cells were
induced in 26-40 % of patients across all dose levels
• Two patients at the 2 mg dose level experienced a
decrease in the CA 15.3 level of 29.5 % and 37.6 %
• A correlation was found between development of
anti-MUC1 antibodies and T-cells with stabilization or
decrease of CA15.3
de Bono et al Annals of Oncology 2004; 15:1825-1833
Antibodies as Immune Modulators:
Conclusion
Injection of antibodies against tumor
association antigens can induce antigen
specific T cell response (through cross
presentation) which also correlates with
clinical response
Oregovomab For The Treatment
of Advanced Ovarian Cancer
Ovarian Cancer & CA125
The Therapeutic Demand
• Common and Fatal: this is the fifth most common cause of cancer death
in women in the US with the highest mortality rate of gynecological
tumors
• Late Diagnosis: approximately 70% of patients present with advanced
disease (Stage III/IV) at the time of diagnosis
• Poor Prognosis: the 5 year survival rate is 20% for stage III, and only 5%
for stage IV
• No Cure: treatment includes surgery, chemotherapy
• Need for an effective low toxicity therapy that leads to a longer better life
CA125 is large glycosylated protein, also known as MUC16
• Expressed on cell surface of serous epithelial ovarian cancer cells
• Shed into the circulation
• Used in diagnosis and to monitor progress of disease and
treatment
Lead Product: Oregovomab (MAb-B43.13)
for CA125 Associated Cancer
• Antigen specificity
– CA125
• Isotype
– Mouse IgG1κ
• Affinity
– 1.1x1010 M-1 for CA125 antigen
• Immunohistochemistry
– Stains specifically ovarian and pancreatic carcinomas
expressing CA125
• No direct effects (ADCC, CDC, receptor blockage)
Oregovomab Initial Clinical Studies
(Done by Unither Pharmaceuticals)
Oregovomab Clinical Studies Findings
• Mono-Immunotherapy is not ideal for Ovarian
Cancer Treatment
• Need for serum Antigen for Antibody Antigen
Complex Formation (Cross Presentation)
• Correlations between Antigen Specific T Cells
(ELISPOT) and Survival
• Chemotherapy Enhances Immune Response
Combinatorial Immunotherapy:
The New Frontier
• Immunotherapy induces minimal toxicity
• Can act independent of concomitant therapies
• Can be used in combination with conventional
therapies such as chemotherapy, local radiation of
tumor, small molecule targeted therapy,
photodynamic therapy, etc.
• Can be used in combination with other immune
modulating therapies such as immunoadjuvants,
check point inhibitors, T cell adaptive transfer
therapy, Danger Signals, etc.
Chemotherapy Enhances Immune
Response
Positive Immune Interaction In Vitro with Taxol for Induction of
CTL Activity Compared to Drug Alone and Necrotic Cells
CTL Assay
70
B43.13
TAXOL
% Specific Lysis
60
TAXOL+B43.13
FREEZE/THAW
50
FREEZE/THAW+B43.13
40
UNLOADED DC
30
20
10
0
75:1
25:1
8:1
Effector:Target Ratio
2.5:1
MAb AR20.5 Therapeutic Animal
Model
• MUC1-Transgenic Mouse
– Developed by Dr. Gendler, Mayo Clinic, Scottsdale, AZ
– C57BL/6 mice that express human MUC1 in tissuespecific fashion
– MUC1-transgenic mice without tumor to optimize the
immunization protocol
– MUC1-transgenic mice with orthotopic and
subcutaneous transplantable tumors (Panc02.MUC1)
and spontaneously developing tumors for tumor
control studies
MAb AR20.5 Chemo-enhanced
Immunotherapy Potential with Gemcitabine
Human MUC1 Transgenic Mice with Subcutaneous Panc02.MUC1 Tumor Model
Chemo-enhanced Immunotherapy:
Drug Specific Enhancement
Immune Function
Drugs
Increased antigen cross-presentation
Gemcitabine
Activation of dendritic cells
Paclitaxel
Homeostatic proliferation
Alkylating agents, fludarabine
Increased homing to tumors
Gemcitabine, antivascular flavonoids
Inhibition of immunosuppressive cells
Gemcitabine, cyclophosphamide, taxanes
Upregulation of recognition molecules
Cisplatin, 5-FU, 5-aza-2’ deoxycitidine
General immune system stimulation from
“danger signal” release from dying tumor
cells
All cytotoxic drugs
Baxeuanis et al Cancer Immunol immunother (2009) 8:317-24
New Perspective:
Cytotoxics are Immune Modulators
• Cytotoxics induce apoptosis and favorable
antigen presentation of tumor
• Cytotoxics can reduce Regulatory T cell Burden
• Cytotoxics can influence the character of an
induced response in an agent specific manner.
Chemo-enhanced
immunotherapy in Advanced
Ovarian Cancer Patients:
A Phase II Clinical Study
Oregovomab Chemo Enhanced Immunotherapy
Front-line Chemo-enhanced Immunotherapy Pilot Phase II Study Design
Presumptive Stage III/IV Ovarian Cancer
Surgery (Staging Laparotomy)
Randomization and Treatment
A
B
Ovarian Cancer
Diagnosis
Informed
Cycle 1
Consent Tumor / Node /
Ascites Collection
A
Cycle 2
Cycle 3
Endpoint for Primary Analysis
B
A
Cycle 4
Cycle 5
B
A
B
Cycle 6
Cycle 7
Cycle 8
12 Weeks
Past
Cycle 5
A
B
24 Weeks
Past
Cycle 5
Follow-Up
6 additional
OvaRex® doses
Up to 2 Years
Lab Sample Collection
A
Routine Testing: baseline, prior to cycle 3, cycle 5, cycle 5 plus 24 weeks
PBMC Collection: pre-surgery, prior to cycle 5, cycle 5 plus 24 weeks
Immune Testing: pre-surgery, baseline, prior to cycle 3, cycle 5, cycle 5 plus 24 we eks
Arm A: OvaRex® concurrent with Carboplatin/Paclitaxel
n=20
B
Arm B: OvaRex® 8-Days After Carboplatin/Paclitaxel
n=20
Arm A: concurrent with chemotherapy (Treatment)
Arm B: one week following chemotherapy (Control)
Braly et al J Immunother 2009;32:54–65
Oregovomab Chemo Enhanced Immunotherapy
Front-Line Chemo-enhanced Immunotherapy Pilot Phase II Study: Kinetics of
Immune Response with Chemo-immunotherapy, Influence of Dose Schedule and
Comparison to Previous Maintenance Study
Arm A: concurrent with chemotherapy (Treatment)
Arm B: one week following chemotherapy (Control)
Braly et al J Immunother 2009;32:54–65
Oregovomab Chemo Enhanced Immunotherapy
Front-Line Chemo-enhanced Immunotherapy Pilot Phase II Study: KaplanMeier Curves of Progression-Free Survival by Treatment Arm (ITT)
Unither Pharmaceuticals
Protocol OVA-Gy-18
Figure 14.2.9.1b Progression Free Survival, Kaplan-Meier Plot (ITT Population)
Progression-Free Survival > 12 months
1.00
O
Survival Distribution Function
100
80
60
40
20
O O OO
O
O O O
0.75
OO
O
OO
O
O
0.50
OOO
O
O
O
0.25
0.00
0
5
10
15
20
25
Time (months)
0
STRATA:
Arm A
Arm B
Overall
GROUP=ArmA
GROUP=ArmB
O O O Censored GROUP=ArmA
O O O Censored GROUP=ArmB
S OU R C E : P :\U N ITH E R \OV A 18\B IOS TA TIS TIC S \FIGU R E S \F_14.2.9.1P FS .S A S
Arm A: concurrent with chemotherapy (Treatment)
Arm B: one week following chemotherapy (Control)
Braly et al J Immunother 2009;32:54–65
D A TE : 8:06/20FE B 2007
Oregovomab Chemo Enhanced Immunotherapy
Arm A: concurrent with
Arm B: one week following
chemotherapy (Treatment)
chemotherapy (Control)
200
200
175
175
IFN- Spots/105 Cells
IFN- Spots/105 Cells
Front-line Chemo-enhanced Immunotherapy Pilot Phase II Study:
CA125-specific T cell Immune Response
150
125
100
75
50
25
150
125
100
75
50
25
0
0
Pre
Post
44%
Braly et al J Immunother 2009;32:54–65
Pre
Post
21%
Oregovomab Chemo Enhanced Immunotherapy
Front-line Chemo-enhanced Immunotherapy Pilot Phase II Study: Favorable
Clinical Outcome Correlates to Generation of CA125-specific T-cell Response
CA125-Specific T cell Response
CA125-Specific T cell Responses
125
125
Percent survival
Percent PFS
100
75
50
25
responders
non-responders
100
75
50
25
0
0
0
10
20
30
0
10
20
Time (months)
Time (months)
Responders n=11, Non-responders n=24
Braly et al J Immunother 2009;32:54–65
30
Oregovomab Chemo Enhanced Immunotherapy
Study OVA-Gy-12: CA125 Tumor Specific T Cell Induction
Associated with Survival Advantage
Recurrent /Refractory
Disease Population
Responders n=11, Non-responders n=7
Gordon et al, 2004
Oregovomab Chemo Enhanced Immunotherapy
Conclusion
Chemotherapy can be immune enhancing, in a
schedule dependent fashion
Correlation between T cell response and survival
Substantial clinical development supported by phase
III product manufacturing development
Excellent safety profile
Positive clinical data to continue the front-line chemoimmunotherapy study
Oregovomab Chemo Enhanced Immunotherapy
Ongoing Clinical Study
Objective:
•Confirm clinical signals suggested in Pilot Phase II
Oregovomab study to justify a definitive phase III study
Design:
•Randomized parallel prospective study of standard
chemotherapy vs. standard of care chemotherapy plus
oregovomab
Patients:
•Newly Diagnosed Stage III/IV CA125 associated Epithelial
Ovarian Cancer who have been optimally cytoreduced
(n=80)
Oregovomab Chemo Enhanced Immunotherapy
Ongoing Clinical Study
Treatment:
• Standard of Care Carboplatin Paclitaxel chemotherapy x
6 cycles vs. Standard of Care Carboplatin Paclitaxel
chemotherapy x 6 cycles with oregovomab 2mg IV
infused at cycle 1, 3, 5 and then at cycle 5 plus 12 weeks
Endpoints:
•
•
•
•
•
•
Safety Profile
CA125 specific ELISPOT
Antibody response (HAMA)
DTH to oregovomab
Progression free survival
Survival
Oregovomab Chemo Enhanced Immunotherapy
Ongoing Clinical Study
Principle Investigator:
•Prof Roberto Angioli (University Campus Bio-Medico of Rome)
CRO:
•Dimensione Ricerca, Rome
Advisors:
•Prof Sergio Pecorelli (AIFA)
•Prof Jonathan Berek (Stanford)
Clinical Advisory Board:
•Dr. Christopher Nicodemus (AIT, US)
•Professor William McGuire (Inova Fairfax Hospital, US)
•Professor Ignace Vergote (Catholic University of Leuven, Belgium)
•Professor Thomas Ehlen (UBC, Canada)
Oregovomab Chemo Enhanced Immunotherapy
Ongoing Clinical Study – Clinical Centers
Center
Policlinico Universitario Campus Bio-Medico, Roma
Università Cattolica del Sacro Cuore Policlinico, Roma
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Università degli Studi di Brescia Azienda Ospedaliera, Brescia
Policlinico di Roma “Umberto I”, Roma
Investigator
Dr. Angioli
Dr. Scambia
Dr. Raspagliesi
Dr. Tognon
Dr. Benedetti Panici
Struttura Complessa di Oncologia Ospedale San Pietro – Fatebenefratelli, Roma
Dr. Pavese
Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo
Dr. Frigerio
Azienda Ospedaliera Cannizzaro di Catania
Catania
Dr. Scollo
University Of Connecticut Health Center, US
Dr. Molly Brewer
Michiana Hematology and Oncology , US
Dr. Michael Method
Stanford Cancer Center, US
Dr. Jonathan Berek
Women Cancer Care, US
Dr. Patricia Braly
Oregovomab Positioning
and Differentiation
• Potential Competition
– Targeted Antibodies: Avastin, Farletuzumab
– Targeted Inhibitors: mTor, PARP Inhibitors
• Oregovomab is capable of stimulating the patient’s
own immune system giving a long lasting effect
• Novel mechanism of action that targets CA125 tumor
marker to elicit T-cells that attack the cancer
• Should benefit from recent advances in
immunotherapy area
• Benign well tolerated safety profile
• Good quality of life for patients undergoing therapy
Oregovomab Positioning
and Differentiation
• Relatively simple dose schedule and administration
– Twenty minute low-dose (2mg) IV infusion 4 – 5 times per
year
• Orphan Drug Designation in US and Europe
• Fast Track Designation in US; will seek accelerated
approval based on PFS and/or tumor specific T cell
stimulation
• Pricing flexibility as Cost of Goods per vial is approximately
$150
• Target front-line combination chemo-immunotherapy
followed by recurrent disease in combination with
chemotherapy
• Expand the market to other CA125 expressing tumors
such as pancreatic cancer
Oregovomab Manufacturing Summary
(Cell Culture Process Validated at 500 L Scale)
Oregovomab Manufacturing Summary
(Downstream Process Validated at 500 L Scale)
Select Publications
Author
Journal
Reference
Topic
Braly et al
Journal of Immunotherapy
2009;32:54–65
Front-line Chemo-Enhanced
Immunotherapy
(Study 18)
Gordon et al
Gynecologic Oncology
2004; 94:340-351
Recurrent Chemo-Enhanced
Immunotherapy
Berek et al
Journal of Immunotherapy
2008; 31:207-214
Role of CA-125
de Bono et al
Annals of Oncology
2004; 15:18251833
Anti-MUC1 for T-cells
Response / ELISPOT
Nicodemus et al
Am J Obstet Gynecol
2010; 202(6):
608.e1-8.
Combination with TLR
Agonist
Korbelik et al
Photochem Photobiol
2009; 85:1418-24
Combination with PDT
Quest Immunotherapy Patents
Patent
Number
Title
Date
US 8,038,994
Combination therapy for treating disease
October 18, 2011
US 7,361,346
Therapeutic compositions that produce an immune response
April 22, 2008
US 7,318,921
Therapeutic compositions that alter the immune response
January 15, 2008
EU 1,357,944
Perylenequinones for Use with Immunotherapy Agents
June 13, 2007
US 6,881,405
Reagents and methods for inducing an immune response to prostate
specific antigen
April 19, 2005
US 6,716,966
Therapeutic binding agents against MUC-1 antigen and methods for
their use
April 6, 2004
US 6,241,985
Therapeutic method and composition utilizing antigen-antibody
complexation and presentation by dendritic cells
February 10, 2004
US 6,241,985
Method and composition for reconforming multi-epitopic antigens to
initiate an immune response
June 5, 2001
US 6,086,873
Therapeutic composition and method of treatment
July 11, 2000
Second Generation of Antibody
for Immunotherapy
Monoclonal IgE to Cancer Antigens
IgE: Another Class of Antibody
•
•
•
•
•
•
Plays an important role in allergy
Associated with adaptive defense
to parasitic organisms
Least abundant circulating blood
levels among Igs; shares the
common light chain of (λ or Κ)
Elicits an immune response by
binding to Fc receptors
High binding affinity for its Fc
receptors compared to IgG
No monoclonal IgE on the market
Monoclonal IgE  Next generation antibody therapeutics
Monoclonal IgE For Immunotherapy
•
Inverse correlation between IgE level/allergic history and
selected malignancies
•
Chronic anti-IgE therapy associated with increased risk of
malignancy
• Polyclonal IgE levels correlated with survival in multiple
myeloma patients
•
IgE positive cellular infiltrate in H&N cancer
• Specific serum IgE cytotoxic in Pancreatic CA
Daniels et al, “The IgE antibody and its use in cancer immunotherapy” in “Cancer and IgE: Introducing
the Concept of AllergoOncology” by Penichet, Manuel L.; Jensen-Jarolim, Erika (Eds.) Springer 2010
Proposed Pathways for IgE : Anti-Cancer Effect
•
Tumor specific IgE cause type I hypersensitivity at
tumor site, causes local vasodilation and leakage
bringing cytotoxic mediators directly to tumor…The
antibody will enhance the effects of standard cancer
treatments
•
IgE-tumor antigen immune complexes result in
enhanced T cell immunity to the antigen
•
ADCP (antibody dependent cell mediated
phagocytosis) and ADCC (antibody dependent cell
mediated cytoxicity) via relevant Fc-epsilon bearing
effectors (including Monocytes, Dendritic cells, Mast
cells, Basophils, Eosinophils) (invoking pathways of
parasite host defense to fight cancer)
Tumor Protection with Therapeutic anti-Her2 IGE MAb
demonstrated In initial animal model studies
Combined HER2 IgE Data (8-18-10)
HBSS
Anti-HER2/neu IgE
100
75
50
25
0
0
20
Percent Survival
Percent survival
125
45
100
75
50
25
70
95
120
Days after D2F2/E2 Challenge
15
25
35
45
Days after D2F2/E2 Challenge
60
110
# of animals
Median
survival
HBSS
17
28
Anti-HER2/neu IgE
18
39
Daniels et al, Can. Imm . Immunother. Epub Nov 30, 2011
Anti-PSA IgE (A200)Improves Survival
CT-26-PSA Tumor Cell Challenged (FcɛRI Transgenic Mouse Model)
Daniels et al AACR 2013 & BMC Cancer 2013 in press
Anti-MUC1 IgE 3C6 Delayed Tumor Growth
4T1.hMUC1 Tumor Cell Challenged (hFcɛRI Tg+ Mouse Model)
Teo et al Cancer Immunology & Immunotherapy 2012
Combinatory Immunotherapy
with addition of
TLR Stimulation
(Danger Signals)
TLR3 and Cancer
Toll-like receptor-3 as a target to enhance
bioactivity of cancer (Nicodemus et al, Am J Obstet
•
•
•
•
•
Gynecol 2010;202:608.e1-8)
DC Maturation and T cell stimulation
– Augmentation of Oregovomab preclinical effects
Local cytokine induction
Specific B and T cell stimulation to PSA in transgenic-PSA mouse
vaccination model
Augmentation of NK mediated cytotoxicity with rituximab
Potential to further enhance activity of all Quest immunotherapy
products.
Combinatory Immunotherapy with
Photosensitizers
• Combination with Photodynamic Therapy
• Generation of local free radicals to enhance
immune effector pathways
Hypocrellin: A Cytotoxic Multisensitizer
Ultrasound
Mechanism of Action
Light
O
OH
OCH3
H3CO
CH3
H3CO
 Induces tissue and cellular
necrosis and apoptotic cell
death
CH3
OCHO
3
O
-
OH
O2
HO2
H2O2
H 2 O2
 Produces activated oxygen
species and free radical
cascade
.
ROS
 Modulates host’s immune
response
Survival Curves for Various Hypocrellin
Formulations Targete Liposomes
(MUC1 Transfectoma Model)
US Patent 7147850
EU Patent 1204423
SUMMARY
• Antibodies modulate immunity to patient’s own
tumor, by targeting tumor derived antigen
• Carboplatin/Paclitaxel treatment enhances immunity
in front-line ovarian cancer setting
• Quest PharmaTech is using combinatorial therapies to
better mobilize anti-tumor immunity
• Late stage product for ovarian cancer with excellent
safety profile; and diversified product pipeline of IgG
and IgE candidates
• Ongoing, risk mitigating clinical trials will confirm the
optimal combination with chemotherapy leading to
design of product registration trial
SUMMARY (Continued)
• Quest PharmaTech has strong patent protection for
its chemo-enhanced immunotherapy approach for
the treatment of cancer
• Monoclonal IgE is a novel antibody approach to
inducing immunity and targeting stroma. Compatible
with concurrent IgG therapy.
Quest Immunotherapy Products
Under Development
Madi R. Madiyalakan, PhD
Chief Executive Officer