antibodies as immune modulators: combinatorial immunotherapy of cancer madi r. madiyalakan, phd...
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Antibodies as Immune Modulators:Combinatorial Immunotherapy
of Cancer
Madi R. Madiyalakan, PhDChief 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 ComplexCA125 conjugated with
FITC (green) pre-incubated with MAb-
B43.13-Cy3 (red)added to day 5 DC for 30
min. before fixation; yellow: co-localized
complex
Antibodies as ImmunemodulatorsAnti-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 IImmunological 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 & CA125The 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
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75:1 25:1 8:1 2.5:1
Effector:Target Ratio
% S
pe
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ys
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B43.13
TAXOL
TAXOL+B43.13
FREEZE/THAW
FREEZE/THAW+B43.13
UNLOADED DC
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 tissue-
specific 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
Ovarian CancerInformed Consent
Endpoint for Primary Analysis
Arm A: OvaRex® concurrent with Carboplatin/Paclitaxeln=20
A
Arm B: OvaRex® 8-Days After Carboplatin/Paclitaxeln=20
B
Lab Sample CollectionRoutine Testing: baseline, prior to cycle 3, cycle 5, cycle 5 plus 24 weeksPBMC Collection: pre-surgery, prior to cycle 5, cycle 5 plus 24 weeksImmune Testing: pre-surgery, baseline, prior to cycle 3, cycle 5, cycle 5 plus 24 weeks
A A A A AB B BB B
DiagnosisCycle 1
Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7 Cycle 812 WeeksPastCycle 5
24 WeeksPastCycle 5
Follow-Up6 additionalOvaRex® dosesUp to 2 Years
Tumor / Node /Ascites Collection
Surgery (Staging Laparotomy)Randomization and Treatment
Presumptive Stage III/IV Ovarian Cancer
Ovarian CancerInformed Consent
Endpoint for Primary Analysis
Arm A: OvaRex® concurrent with Carboplatin/Paclitaxeln=20
A
Arm B: OvaRex® 8-Days After Carboplatin/Paclitaxeln=20
B
Arm A: OvaRex® concurrent with Carboplatin/Paclitaxeln=20
A Arm A: OvaRex® concurrent with Carboplatin/Paclitaxeln=20
A
Arm B: OvaRex® 8-Days After Carboplatin/Paclitaxeln=20
B Arm B: OvaRex® 8-Days After Carboplatin/Paclitaxeln=20
B
Lab Sample CollectionRoutine Testing: baseline, prior to cycle 3, cycle 5, cycle 5 plus 24 weeksPBMC Collection: pre-surgery, prior to cycle 5, cycle 5 plus 24 weeksImmune Testing: pre-surgery, baseline, prior to cycle 3, cycle 5, cycle 5 plus 24 weeks
Lab Sample CollectionRoutine Testing: baseline, prior to cycle 3, cycle 5, cycle 5 plus 24 weeksPBMC Collection: pre-surgery, prior to cycle 5, cycle 5 plus 24 weeksImmune Testing: pre-surgery, baseline, prior to cycle 3, cycle 5, cycle 5 plus 24 weeks
A A A A AB B BB B
DiagnosisCycle 1
Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7 Cycle 812 WeeksPastCycle 5
24 WeeksPastCycle 5
Follow-Up6 additionalOvaRex® dosesUp to 2 Years
Tumor / Node /Ascites Collection
Surgery (Staging Laparotomy)Randomization and Treatment
Presumptive Stage III/IV Ovarian Cancer
Front-line Chemo-enhanced Immunotherapy Pilot Phase II Study Design
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 ImmunotherapyFront-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: Kaplan-Meier Curves of Progression-Free Survival by Treatment Arm (ITT)
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Arm A Arm B Overall
Progression-Free Survival > 12 months Unither PharmaceuticalsProtocol OVA-Gy-18
Figure 14.2.9.1b Progression Free Survival, Kaplan-Meier Plot (ITT Population)
SOURCE: P:\UNITHER\OVA18\BIOSTATISTICS\FIGURES\F_14.2.9.1PFS.SAS DATE: 8:06/20FEB2007
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STRATA: GROUP=Arm A Censored GROUP=Arm AGROUP=Arm B Censored GROUP=Arm B
O O OO O O
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: CA125-specific T cell Immune Response
Pre Post0
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IFN
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ells
Pre Post0
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44%
Arm A: concurrent with
chemotherapy (Treatment)
Arm B: one week following
chemotherapy (Control)
21%
Braly et al J Immunother 2009;32:54–65
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 Responses
0 10 20 300
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Time (months)
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CA125-Specific T cell Response
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Time (months)
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Responders n=11, Non-responders n=24
Braly et al J Immunother 2009;32:54–65
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 chemo-immunotherapy study
Oregovomab Chemo Enhanced ImmunotherapyOngoing Clinical Study
Objective: • Confirm clinical signals suggested in Pilot Phase II
Oregovomab study to justify a definitive phase III studyDesign: • 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 ImmunotherapyOngoing 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 ImmunotherapyOngoing 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 ImmunotherapyOngoing Clinical Study – Clinical Centers
Center InvestigatorPoliclinico Universitario Campus Bio-Medico, Roma Dr. Angioli
Università Cattolica del Sacro Cuore Policlinico, Roma Dr. Scambia
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano Dr. Raspagliesi
Università degli Studi di Brescia Azienda Ospedaliera, Brescia Dr. Tognon
Policlinico di Roma “Umberto I”, Roma 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 CataniaCatania
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;32:54–65Front-line Chemo-Enhanced Immunotherapy(Study 18)
Gordon et al Gynecologic Oncology 2004; 94:340-351Recurrent Chemo-Enhanced Immunotherapy
Berek et al Journal of Immunotherapy 2008; 31:207-214 Role of CA-125
de Bono et al Annals of Oncology2004; 15:1825-1833
Anti-MUC1 for T-cells Response / ELISPOT
Nicodemus et al Am J Obstet Gynecol2010; 202(6): 608.e1-8.
Combination with TLR Agonist
Korbelik et al Photochem Photobiol 2009; 85:1418-24 Combination with PDT
Quest Immunotherapy PatentsPatent
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)
# of animals Median survival
HBSS 17 28
Anti-HER2/neu IgE 18 39
15 25 35 45 60Days after D2F2/E2 Challenge
Combined HER2 IgE Data (8-18-10)
00
25
50
75
100
125HBSS
Anti-HER2/neu IgE
20 45 70 95 120
Days after D2F2/E2 Challenge
Pe
rc
en
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urv
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Per
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urv
ival 100
75
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25
110
Tumor Protection with Therapeutic anti-Her2 IGE MAb demonstrated In initial animal model studies
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 CancerToll-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
Mechanism of Action Produces activated
oxygen species and free radical cascade
Induces tissue and cellular necrosis and apoptotic cell death
Modulates host’s immune response
OH
OCH3
O
H3CO
H3CO
O OH
OCH3
CH3
O
CH3
Ultrasound
ROS
Light
O-2
H2O2
HO2 .
H2O2
Survival Curves for Various Hypocrellin Formulations Targete Liposomes
(MUC1 Transfectoma Model)
US Patent 7147850EU 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, PhDChief Executive Officer